Heterocyclic derivatives as pi3k inhibitors

ABSTRACT

or pharmaceutically acceptable salts thereof, which are inhibitors of PI3K-γ which are useful for the treatment of disorders such as autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases.

TECHNICAL FIELD

The present disclosure provides derivatives of heterocyclic compoundsthat modulate the activity of phosphoinositide 3-kinases-gamma (PI3Kγ)and are useful in the treatment of diseases related to the activity ofPI3Kγ including, for example, autoimmune diseases, cancer,cardiovascular diseases, and neurodegenerative diseases.

BACKGROUND

The phosphoinositide 3-kinases (PI3Ks) belong to a large family of lipidsignaling kinases that phosphorylate phosphoinositides at the D3position of the inositol ring (Cantley, Science, 2002,296(5573):1655-7). PI3Ks are divided into three classes (class I, II,and III) according to their structure, regulation and substratespecificity. Class I PI3Ks, which include PI3Kα, PI3Kβ, PI3Kγ, andPI3Kδ, are a family of dual specificity lipid and protein kinases thatcatalyze the phosphorylation of phosphatidylinosito-4,5-bisphosphate(PIP₂) giving rise to phosphatidylinosito-3,4,5-trisphosphate (PIP₃).PIP₃ functions as a second messenger that controls a number of cellularprocesses, including growth, survival, adhesion and migration. All fourclass I PI3K isoforms exist as heterodimers composed of a catalyticsubunit (p110) and a tightly associated regulatory subunit that controlstheir expression, activation, and subcellular localization. PI3Kα,PI3Kβ, and PI3Kδ associate with a regulatory subunit known as p85 andare activated by growth factors and cytokines through a tyrosinekinase-dependent mechanism (Jimenez, et al., J Biol Chem., 2002,277(44):41556-62) whereas PI3Kγ associates with two regulatory subunits(p101 and p84) and its activation is driven by the activation ofG-protein-coupled receptors (Brock, et al., J Cell Biol., 2003,160(1):89-99). PI3Kα and PI3K3 are ubiquitously expressed. In contrast,PI3Kγ and PI3K8 are predominantly expressed in leukocytes(Vanhaesebroeck, et al., Trends Biochem Sci., 2005, 30(4):194-204).

Expression of PI3Kγ is mainly restricted to hematopoietic system,although it can be also detected at lower level in endothelium, heartand brain. PI3Kγ knock-out or kinase dead knock in mice are normal andfertile and do not present any overt adverse phenotypes. Analysis at thecellular level indicates that PI3Kγ is required for GPCR ligand-inducedPtdINs (3,4,5)P3 production, chemotaxis and respiratory burst inneutrophils. PI3Kγ-null macrophages and dendritic cell exhibit reducedmigration towards various chemoattractants. T-cells deficient in PI3Kγshow impaired cytokine production in response to anti-CD3 or Con Astimulation. PI3Kγ working downstream of adenosine A3A receptor iscritical for sustained degranulation of mast cells induced by FCεRIcross-linking with IgE. PI3Kγ is also essential for survival ofeosinophils (Ruckle et al., Nat. Rev. Drug Discovery, 2006, 5, 903-918)

Given its unique expression pattern and cellular functions, thepotential role of PI3Kγ in various autoimmune and inflammatory diseasemodels has been investigated with genetic and pharmacological tools. Inasthma and allergy models, PI3Kγ^(−/−) mice or mice treated with PI3Kγinhibitor showed a defective capacity to mount contact hypersensitivityand delayed-type hypersensitivity reactions. In these models, PI3Kγ wasshown to be important for recruitment of neutrophils and eosinopohils toairways and degranulation of mast cells (see e.g. Laffargue et al.,Immunity, 2002, 16, 441-451; Prete et al., The EMBO Journal, 2004, 23,3505-3515; Pinho et al., L. Leukocyte Biology, 2005, 77, 800-810; Thomaset al., Eur. J Immunol. 2005, 35, 1283-1291; Doukas et al., J Pharmacol.Exp Ther. 2009, 328, 758-765).

In two different acute pancreatitis models, genetic ablation of PI3Kγsignificantly reduced the extent of acinar cell injury/necrosis andneutrophil infiltration without any impact on secretive function ofisolated pancreatic acini (Lupia et al., Am. J Pathology, 2004, 165,2003-2011). PI3Kγ^(−/−) mice were largely protected in four differentmodels of rheumatoid arthritis (CIA, α-CII-IA, K/BxN serum transfer andTNF transgenic) and PI3Kγ inhibition suppressed the progression of jointinflammation and damage in the CIA and α-CII-IA models (see e.g., Campset al., Nat. Medicine, 2005, 11, 939-943; Randis et al., Eur. J Immunol,2008, 38, 1215-1224; Hayer et al., FASB J, 2009, 4288-4298). In theMRL-lpr mouse model of human systemic lupus erythematous, inhibition ofPI3Kγ reduced glomerulonephritis and prolonged life span (Barber et al.,Nat. Medicine, 2005, 9, 933-935).

There is evidence suggesting that chronic inflammation due toinfiltration by myeloid-derived cells is a key component in theprogression of neurodegeneration diseases, such as Alzheimer's disease(AD) (Giri et al., Am. J. Physiol. Cell Physiol., 2005, 289, C264-C276;El Khoury et al., Nat. Med., 2007, 13, 432-438). In line with thissuggestion, PI3Kγ inhibition was shown to attenuate Aβ(1-40)-inducedaccumulation of activated astrocytes and microglia in the hippocampusand prevent the peptide-induced congnitive deficits and synapticdysfunction in a mouse model of AD (Passos et al., Brain Behav. Immun.2010, 24, 493-501). PI3Kγ deficiency or inhibition also was shown todelay onset and alleviate symptoms in experimental autoimmuneencephalomyelitis in mice, a mouse model of human multiple sclerosis,which is another form of neurodegeneration disease (see e.g., Rodrigueset al., J. Neuroimmunol. 2010, 222, 90-94; Berod et al., Euro. J.Immunol. 2011, 41, 833-844; Comerford et al., PLOS one, 2012, 7, e45095;Li et al., Neuroscience, 2013, 253, 89-99).

Chronic inflammation has been formally recognized as one of thehallmarks for many different types of cancers. Accordingly, selectiveanti-inflammatory drugs represent a novel class of anti-cancer therapies(Hanahan and Weinberg, Cell, 2011, 144, 646-674). Since PI3Kγ isreported to mediate various inflammatory processes, its role as animmune oncology target has also been investigated. A recent studyreported that PI3Kγ deficiency suppressed tumor growth in the syngeneicmodels of lung cancer, pancreatic cancer and melanoma (LLC, PAN02 andB16). PI3Kγ deficiency or inhibition also inhibited tumor growth in aspontaneous breast cancer model (Schmid et al., Cancer Cell, 2011, 19,715-727). A further study reported that PI3Kγ deficiency couldameliorate inflammation and tumor growth in mice havingcolitis-associated colon cancer, (Gonzalez-Garcia et al.,Gastroenterology, 2010, 138, 1373-1384). Detailed mechanistic analysisindicates that tumor infiltration by CD11b⁺ myeloid cells can causeprotumorigenic inflammation at tumor sites and PI3Kγ in the myeloidcells is critical in mediating signaling of various chemoattractants inbring the cells to the tumor (Schmid et al., Cancer Cell, 2011, 19,715-727). Other studies suggest that PI3Kγ is also required fordifferentiation of naïve myeloid cells into M2 macrophges at tumorsites. M2 macrophages promote tumor growth and progression by secretingimmunosuppressive factors such arginase 1, which depletes the tumormicroenvironment of arginine, thereby promoting T-cell death and NK cellinhibition (Schmidt et al., Cancer Res. 2012, 72 (Suppl 1: Abstract,411; Kaneda et al., Cancer Res., 74 (Suppl 19: Abstract 3650)).

In addition to its potential role in promoting protumorigenicmicroenvironment, PI3Kγ may play a direct role in cancer cells. PI3Kγ isreported to be required for signaling from the Kaposi'ssarcoma-associated herpevirus encoded vGPCR oncogene and tumor growth ina mouse model of sarcoma (Martin et al., Cancer Cell, 2011, 19,805-813). PI3Kγ was also suggested to be required for growth of T-ALL(Subramanjam et al., Cancer Cell, 2012, 21, 459-472), PDAC and HCC cells(Falasca and Maffucci, Frontiers in Physiology, 2014, 5, 1-10).Moreover, in a survey of driver mutations in pancreatic cancer, PI3Kγgene was found to contain second highest scoring predicted drivenmutation (R839C) among the set of genes not previously identified as adriver in pancreatic cancer (Carter et al., Cancer Biol. Ther. 2010, 10,582-587).

Finally, PI3Kγ deficiency also has been reported to offer protection toexperimental animals in different cardiovascular disease models. Forexamples, lack of PI3Kγ would reduce angiotension-evoked smooth musclecontraction and, therefore, protect mice from angiotension-inducedhypertension (Vecchione et al., J Exp. Med. 2005, 201, 1217-1228). Inrigorous animal myocardial infarction models, PI3Kγ inhibition providedpotent cardioprotection, reducing infarct development and preservingmyocardial function (Doukas et al., Proc. Natl. Acad. Sci. USA, 2006,103, 19866-19871).

For these reasons, there is a need to develop new PI3Kγ inhibitors thatcan be used for the treatment of diseases such as cancer, autoimmunedisorders, and inflammatory and cardiac diseases. This application isdirected to this need and others.

SUMMARY

The present disclosure relates to, inter alia, compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein constituentmembers are defined herein.

The present disclosure further provides pharmaceutical compositionscomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present disclosure further provides methods of inhibiting anactivity of PI3Kγ kinase comprising contacting the kinase with acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

The present disclosure further provides methods of treating a disease ora disorder associated with abnormal PI3Kγ kinase expression or activityin a patient by administering to said patient a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

The present disclosure further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present disclosure further provides use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the preparationof a medicament for use in any of the methods described herein.

DETAILED DESCRIPTION

Compounds The present application provides, inter alia, compounds ofFormula (I):

or a pharmaceutically acceptable salt thereof; wherein:

each bond symbol represented by

is independently a single or double bond;

R¹ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a1), SR^(a1),NHOR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)NR^(c1)(OR^(a1)),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NOH)R^(b1),C(═NCN)R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NOH)NR^(c1)R^(d1),NR^(c1)C(═NCN)NR^(c1)R^(d1), NR^(e1)C(═NR^(e1))R^(b1),NR^(e1)S(O)NR^(e1)R^(d1), NR^(e1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)(═NR^(e1))R^(b1), NR^(c1)S(O)₂NR^(e1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), S(O)₂NR^(c1)R^(d1),S(O)(═NR^(e1))R^(b1), OS(O)(═NR^(e1))R^(b1), OS(O)₂R^(b1), SF₅,P(O)R^(f1)R^(g1), OP(O)(OR^(h1))(OR^(i1)), P(O)(OR^(h1))(OR^(i1)), andBR^(j1)R^(k1), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R¹ are each optionally substituted with1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(1A) substituents;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a1), R^(b1), R^(c1)and R^(d1) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or8 independently selected R^(1A) substituents;

or, any R^(c1) and R^(d1), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(1A) substituents;

each R^(e1) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f1) and R^(g1) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h1) and R^(i1) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j1) and R^(k1) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j1) and R^(k1) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(1A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a1), SR^(a1),NHOR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)NR^(c11)(OR^(a11)),C(O)OR^(a11), OC(O)R^(b11), OC(O)NR^(c11)R^(d11), NR^(c11)R^(d11),NR^(c11)NR^(c11)R^(d11), NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11),NR^(c11)C(O)NR^(c11)R^(d11), C(═NR^(e11))R^(b11), C(═NOH)R^(b111),C(═NCN)R^(b11), C(═NR^(e11))NR^(c11)R^(d11),NR^(c11)C(═NR^(e11))NR^(c11)R^(d11), NR^(c11)C(═NOH)NR^(c11)R^(d11),NR^(c11)C(═NCN)NR^(c11)R^(d11), NR^(c11)C(═NR^(e11))R^(b11),NR^(c11)S(O)NR^(c11)R^(d11), NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11),NR^(c11)S(O)(═NR^(e11))R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(b1)1, S(O)₂NR^(c11)R^(d11),S(O)(═NR^(e11))R^(b11), OS(O)(═NR^(e11))R^(b11), OS(O)₂R^(b11), SF₅,P(O)R^(f11)R^(g11), OP(O)(OR^(h11))(OR^(i11)), P(O)(OR^(h11))(OR^(i11)),and BR^(j11)R^(k11), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(1A) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(1B)substituents; each R^(a11), R^(b11), R^(c11), and R^(d11) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a11), R^(b11),R^(c11) and R^(d11) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(1B) substituents; or, any R^(c11)and R^(d11), attached to the same N atom, together with the N atom towhich they are attached, form a 5-10 membered heteroaryl group or a 4-10membered heterocycloalkyl group, wherein the 5-10 membered heteroarylgroup or 4-10 membered heterocycloalkyl group is optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(1B)substituents; each R^(e11) is independently selected from H, OH, CN,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,and C₂₋₆ alkynyl;

each R^(f11) and R^(g11) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-; each R^(h11) and R^(i11)is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(j11) and R^(k11) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j11) and R^(k11) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(1B) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a12),SR^(a12), NHOR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12),C(O)NR^(c12)(OR^(a12)), C(O)OR^(a2), OC(O)R^(b12), OC(O)NR^(c12)R^(d2),NR^(c12)R^(d12), NR^(c12)NR^(c12)R^(d12), NR^(c12)C(O)R^(b12),NR^(c12)C(O)OR^(a12), NR^(c12)C(O)NR^(c12)R^(d12), C(═NR^(e12))R^(b12),C(═NOH)R^(b12), C(═NCN)R^(b12), C(═NR^(e12))NR^(c12)R^(d12),NR^(c12)C(═NR^(e12))NR^(c12)R^(d12), NR^(c12)C(═NOH)NR^(c12)R^(d12),NR^(c12)C(═NCN)NR^(c12)R^(d12), NR^(c12)C(═NR^(e12))R^(b12),NR^(c12)S(O)NR^(c12)R^(d12), NR^(c12)S(O)R^(b12), NR^(c12)S(O)₂R^(b12),NR^(c12)S(O)(═NR^(e12))R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12),S(O)R^(b12), S(O)NR^(c12)R^(d12), S(O)₂R^(b12), S(O)₂NR^(c12)R^(d12),S(O)(═NR^(e12))R^(b12), OS(O)(═NR^(e12))R^(b12), OS(O)₂R^(b12), SF₅,P(O)R^(f12)R^(g12), OP(O)(OR^(h12))(OR^(c12)), P(O)(OR^(h12))(OR^(c12)),and BR^(j12)R^(k12), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(1B) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(1C)substituents; each R^(a12), R^(b12), R^(c12), and R^(d12) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a2), R^(b12),R^(c12) and R^(d12) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(1C) substituents;

or, any R^(c12) and R^(d12), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(1C) substituents;

each R^(e12) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f12) and R^(g12) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆-C₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h12) and R^(i12) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆-C₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j12) and R^(k12) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j12) and R^(k12) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(1C) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a13), SR^(a3),NHOR^(a13), C(O)R^(b13), C(O)NR^(c13)R^(d13), C(O)NR^(c13)(OR^(a13)),C(O)OR^(a13), OC(O)R^(b13), OC(O)NR^(c13)R^(d13), NR^(c13)R^(d13),NR^(c13)NR^(c13)R^(d13), NR^(c13)C(O)R^(b13), NR^(c13)C(O)OR^(a13),NR^(c13)C(O)NR^(c13)R^(d13), C(═NR^(e13))R^(b13), C(═NOH)R^(b13),C(═NCN)R^(b13), C(═NR^(e13))NR^(c13)R^(d13),NR^(c13)C(═NR^(e13))NR^(c13)R^(d13), NR^(c13)C(═NOH)NR^(c13)R^(d13),NR^(c13)C(═NCN)NR^(c13)R^(d13), NR^(c13)C(═NR^(e13))R^(b13),NR^(c13)S(O)NR^(c13)R^(d13), NR^(c13)S(O)R^(b13), NR^(c13)S(O)₂R^(b13),NR^(c13)S(O)(═NR^(e13))R^(b13), NR^(c13)S(O)₂NR^(c13)R^(d3),S(O)R^(b13), S(O)NR^(c13)R^(d13), S(O)₂R^(b13), S(O)₂NR^(c13)R^(d13),S(O)(═NR^(e13))R^(b13), OS(O)(═NR^(e13))R^(b13), OS(O)₂R^(b13), SF₅,P(O)R^(f13)R^(g13), OP(O)(OR^(h13))(OR^(i13)), P(O)(OR^(h13))(OR^(i13)),and BR^(j13)R^(k13), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(1C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a13), R^(b13), R^(c13), and R^(d13) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a3), R^(b13), R^(c13) and R^(d13) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

or, any R^(c13) and R^(d13), attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroarylgroup or a 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl group or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e13) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f13) and R^(g13) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h13) and R^(i13) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

each R^(j13) and R^(k13) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j13) and R^(k13) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(M) is independently selected from D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃alkylcarbonyloxy, aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy, di(C₁₋₃alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino;

X² is N or CR²;

R² is selected from H, D, halo, CN, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and C₃₋₇ cycloalkyl, and NH₂;

X⁴ is N or CR⁴;

X⁵ is N or CR⁵;

R³, R⁴ and R⁵ are each independently selected from H, D, halo, CN, OH,NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₆alkoxy-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, and C(O)NR^(a3)R^(b3);

each R^(a3) and R^(b3) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a3) and R^(b3) are eachoptionally substituted with 1, 2, 3 or 4 independently selected R^(M)substituents;

or, any R^(a3) and R^(b3), attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroarylgroup or a 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl group or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

X⁶ is N or CR⁶;

R⁶ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a6), SR^(a6),NHOR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)NR^(c6)(OR^(a6)),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6),NR^(c6)C(O)NR^(c6)R^(d6), C(═NR^(e6))R^(b6), C(═NOH)R^(b6),C(═NCN)R^(b6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), NR⁶C(═NOH)NR^(c6)R^(d6),NR⁶C(═NCN)NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))R^(b6),NR^(c6)S(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)(═NR^(e6))R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), S(O)₂NR^(c6)R^(d6),S(O)(═NR^(e6))R^(b6), OS(O)(═NR^(e6))R^(b6), OS(O)₂R^(b6), SF₅,P(O)R^(f6)R^(g6), OP(O)(OR^(h6))(OR^(i6)), P(O)(OR^(h6))(OR^(i6)), andBR^(j6)R^(k6), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁶ are each optionally substituted with1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(6A) substituents;

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a6), R^(b6), R^(c6)and R^(d6) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or8 independently selected R^(6A) substituents;

or, any R^(c6) and R^(d6), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(6A) substituents;

each R^(e6) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f6) and R^(g6) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h6) and R^(i6) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j6) and R^(k6) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j6) and R^(k6) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(6A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a61),SR^(a61), NHOR^(a61), C(O)R^(b61), C(O)NR^(c61)R^(d61),C(O)NR^(c61)(OR^(a61)), C(O)OR^(a61), OC(O)R^(b61),OC(O)NR^(c61)R^(d61), NR^(c61)R^(d61), NR^(c61)NR^(c61)R^(d61),NR^(c61)C(O)R^(b61), NR^(c61)C(O)OR^(a61), NR^(c61)C(O)NR^(c61)R^(d61),C(═NR^(e61))R^(b61), C(═NOH)R^(b61), C(═NCN)R^(b61),C(═NR^(e61))NR^(c61)R^(d61), NR^(c61)C(═NR^(e61))NR^(c61)R^(d61),NR^(c61)C(═NOH)NR^(c61)R^(d61), NR^(c61)C(═NCN)NR^(c61)R^(d61),NR^(c61)C(═NR^(e61))R^(b61), NR^(c61)S(O)NR^(c61)R^(d61),NR^(c61)S(O)R^(b61), NR^(c61)S(O)₂R^(b61),NR^(c61)S(O)(═NR^(e61))R^(b61), NR^(c61)S(O)₂NR^(c61)R^(d61),S(O)R^(b61), S(O)NR^(c61)R^(d61), S(O)₂R^(b61), S(O)₂NR^(c61)R^(d61),S(O)(═NR^(e61))R^(b61), OS(O)(═NR^(e61))R^(b61), OS(O)₂R^(b61), SF₅,P(O)R^(f61)R^(g61), OP(O)(OR^(h61))(OR^(i61)), P(O)(OR^(h61))(OR^(i61)),and BR^(j61)R^(k61), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(6A) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(6B)substituents;

each R^(a61), R^(b61), R^(c61), and R^(d61) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a61), R^(b61),R^(c61) and R^(d61) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(6B) substituents;

or, any R^(c61) and R^(d61), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(6B) substituents;

each R^(e61) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f61) and R^(g61) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h61) and R^(i61) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j61) and R^(k61) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j61) and R^(k61) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(6B) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆-C₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a62),SR^(a62), NHOR^(a62), C(O)R^(b62)C(O)NR^(c62)R^(d62),C(O)NR^(c62)(OR^(a62)), C(O)OR^(a62), OC(O)R^(b62),OC(O)NR^(c62)R^(d62), NR^(c62)R^(d62), NR^(c62)NR^(c62)R^(d62),NR^(c62)C(O)R^(b62), NR^(c62)C(O)OR^(a62), NR^(c62)C(O)NR^(c62)R^(d62),C(═NR^(e62))R^(b62), C(═NOH)R^(b62), C(═NCN)R^(b62),C(═NR^(e62))NR^(c62)R^(d62), NR^(c62)C(═NR^(e62))NR^(c62)R^(d62),NR^(c62)C(═NOH)NR^(c62)R^(d62), NR^(c62)C(═NCN)NR^(c62)R^(d62),NR^(c62)C(═NR^(e62))R^(b62), NR^(c62)S(O)NR^(c62)R^(d62),NR^(c62)S(O)R^(b62), NR^(c62)S(O)₂R^(b62),NR^(c62)S(O)(═NR^(e62))R^(b62), NR^(c62)S(O)₂NR^(c62)R^(d62),S(O)R^(b62), S(O)NR^(c62)R^(d62), S(O)₂R^(b62), S(O)₂NR^(c62)R^(d62),S(O)(═NR^(e62))R^(b62), OS(O)(═NR^(e62))R^(b62), OS(O)₂R^(b62), SF₅,P(O)R^(f62)R^(g62), OP(O)(OR^(h62))(OR^(i62)), P(O)(OR^(h62))(OR^(i62)),and BR^(j62)R^(k62), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(6B) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(6C)substituents; each R^(a62), R^(b62), R^(c62), and R^(d62) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a62), R^(b62),R^(c62) and R^(d62) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(6C) substituents;

or, any R^(c62) and R^(d62), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(6C) substituents;

each R^(e62) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f62) and R^(g62) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h62) and R⁶² is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j62) and R^(k62) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j62) and R^(k62) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(6C) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a63), SR^(a63),NHOR^(a63), C(O)R^(b63), C(O)NR^(c63)R^(d63), C(O)NR^(c63)(OR^(a63)),C(O)OR^(a63), OC(O)R^(b63), OC(O)NR^(c63)R^(d63), NR^(c63)R^(d63),NR^(c63)NR^(c63)R^(d63), NR^(c63)C(O)R^(b63), NR^(c63)C(O)OR^(a63),NR^(c63)C(O)NR^(c63)R^(d63), C(═NR^(e63))R^(b63), C(═NOH)R^(b63),C(═NCN)R^(b63), C(═NR^(e63))NR^(c63)R^(d63),NR^(c63)C(═NR^(e63))NR^(c63)R^(d63), NR^(c63)C(═NOH)NR^(c63)R^(d63),NR^(c63)C(═NCN)NR^(c63)R^(d63), NR^(c63)C(═NR^(e63))R^(b63),NR^(c63)S(O)NR^(c63)R^(d63), NR^(c63)S(O)R^(b63), NR^(c63)S(O)₂R^(b63),NR^(c63)S(O)(═NR^(e63))R^(b63), NR^(c63)S(O)₂NR^(c63)R^(d63),S(O)R^(b63), S(O)NR^(c63)R^(d63), S(O)₂R^(b63), S(O)₂NR^(c63)R^(d63),S(O)(═NR^(e63))R^(b63), OS(O)(═NR^(e63))R^(b63), OS(O)₂R^(b63), SF₅,P(O)R^(f63)R^(g63), OP(O)(OR^(h63))(OR^(i63)), P(O)(OR^(h63))(OR^(i63)),and BR^(j63)R^(k63), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(6C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a63), R^(b63), R^(c63), and R^(d63) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a63), R^(b63), R^(c63) and R^(d63) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

or, any R^(c63) and R^(d63), attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroarylgroup or a 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl group or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e63) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f63) and R^(g63) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h63) and R⁶³ is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

each R^(j63) and R^(k63) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j63) and R^(k63) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

X⁷ is N, CH, or C;

X⁸ is N, CH, or C;

X⁹ is N, NR⁹N, O, S, S(O), S(O)₂, CR⁹, or C(R⁹)₂;

X¹⁰ is N, NR^(10N), O, S, CR¹⁰, or C(R¹⁰)₂;

X¹¹ is N, NR^(11N), O, S, CR^(u), or C(R¹¹)₂;

wherein no more than three of X⁴, X⁵, X⁶, X⁷, and X⁸ are simultaneouslyN; and

at least two of X⁷, X⁸, X⁹, X¹⁰, and X¹¹ are independently selected fromC, CH, CR⁹, C(R⁹)₂, CR¹⁰, C(R¹⁰)₂, CR^(u), and C(R^(u))₂; and

no two adjacent members of X⁹, X¹⁰, and X¹¹ are simultaneously O, S,S(O), or S(O)₂;

provided that (a) when X⁷ is N, then X⁸ is C; or (b) when X⁷ is C, thenX⁸ is N;

R^(9N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b9N), C(O)NR^(9N)R^(d9)N,C(O)OR^(a9N), C(═NR^(e9N))R^(b9N)C(═NR^(e9)N)NR^(c9N)R^(d9N),C(═NCN)NR^(9N)R^(d9N), C(═NOR^(a9)N)NR^(c9N), S(O)₂R^(b9N),S(O)(═NR⁹N)R^(d9N) and S(O)₂NR^(c9N)R^(d9N), wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(9N) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(9NA) substituents;

each R^(a9N), R^(b9N), R^(c9N), and R^(d9N) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a9N), R^(b9N),R^(c9N), and R^(d9N) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(9NA) substituents;

or, any R^(c9N) and R^(d9N), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(9NA) substituents;

each R^(e9N) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(9NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a9N2), SR^(a9N2),NHOR^(a9N2), C(O)R^(b9N2), C(O)NR^(9N2)R^(d9N2)C(O)NR^(c9N2)(OR^(a9N2)),C(O)OR^(a9N2), OC(O)R^(b9N2), OC(O)NR^(c9N2)R^(d9N2), NR^(c9N2)R^(d9N2),NR^(c9N2)NR^(c9N2)R^(d9N2), NR^(c9N2)C(O)R^(b9N2),NR^(c9N2)C(O)OR^(a9N2), NR^(c9N2)C(O)NR^(c9N2)R^(d9N2),C(═NR^(e9N2))R^(b9N2), C(═NOH)R^(b9N2), C(═NCN)R^(b9N2),C(═NR^(e9N2))NR^(c9N2)R^(d9N2), NR^(c9N2)C(═NR^(e9N2))NR^(c9N2)R^(d9N2),NR^(c9N2)C(═NOH)NR^(c9N2)R^(d9N2), NR^(c9N2)C(═NCN)NR^(c9N2)R^(d9N2)NR^(c9N2)C(═NR^(e9N2))R^(b9N2), NR^(c9N2)S(O)NR^(c9N2)R^(d9N2),NR^(c9N2)S(O)R^(b9N2), NR^(c9N2)S(O)₂R^(b9N2),NR^(c9N2)S(O)(═NR^(e9N2))R^(b9N2), NR^(c9N2)S(O)₂NR^(c9N2)R^(d9N2),S(O)R^(b9N2), S(O)NR^(c9N2)R^(d9N2), S(O)₂R^(b9N2),S(O)₂NR^(c9N2)R^(d9N2), S(O)(═NR^(e9N2))R^(b9N2),OS(O)(═NR^(e9N2))R^(b9N2), OS(O)₂R^(b9N2), SF₅, P(O)R^(f9N2)R^(g9N2)OP(O)(OR^(h9N2))(OR^(i9N2)), P(O)(OR^(h9N2))(OR^(i9N2)), andBR^(9N2)R^(k9N2), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(9NA) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a9N2), R^(b9N2), R^(c9N2), and R^(d9N2) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a9N2), R^(b9N2), R^(c9N2) andR^(d9N2) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents;

or, any R^(c9N2) and R^(d9N2), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-6 memberedheteroaryl group or a 4-7 membered heterocycloalkyl group, wherein the5-6 membered heteroaryl group or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e9N2) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f9N2) and R^(g9N2) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h9N2) and R^(i9N2) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

each R^(j9N2) and R^(k9N2) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j9N2) and R^(k9N2) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R⁹ is independently selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a91), SR^(a91), NHOR^(a91), C(O)R^(b91),C(O)NR^(c91)R^(d91), C(O)NR^(c91)(OR^(a91)), C(O)OR^(a91), OC(O)R^(b91),OC(O)NR^(c91)R^(d91), NR^(c91)R^(d91), NR^(c91)NR^(c91)R^(d91),NR^(c91)C(O)R^(b91), NR^(c91)C(O)OR^(a91), NR^(c91)C(O)NR^(c91)R^(d91),C(═NR^(e91))R^(b91), C(═NOH)R^(b91), C(═NCN)R^(b91),C(═NR^(e91))NR^(c91)R^(d91), NR^(c91)C(═NR^(e91))NR^(c91)R^(d91),NR^(c91)C(═NOH)NR^(c91)R^(d91), NR^(c91)C(═NCN)NR^(c91)R^(d91),NR^(c91)C(═NR^(e91))R^(b91), NR^(c91)S(O)NR^(c91)R^(d91),NR^(c91)S(O)R^(b91), NR^(c91)S(O)₂R^(b91),NR^(c91)S(O)(═NR^(e91))R^(b91), NR^(c91)S(O)₂NR^(c91)R^(d91),S(O)R^(b91), S(O)NR^(c91)R^(d91), S(O)₂R^(b91), S(O)₂NR^(c91)R^(d91),S(O)(═NR^(e91))R^(b91), OS(O)(═NR^(e91))R^(b91), OS(O)₂R^(b91), SF₅,P(O)R^(f91)R^(g91), OP(O)(OR^(h91))(OR^(i91)), P(O)(OR^(h91))(OR^(i91)),and BR^(j91)R^(k91), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁹ are each optionally substituted with1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(9A) substituents;

or, alternatively, two R⁹ groups together form an oxo group;

each R^(a91), R^(b91), R^(c91), and R^(d91) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a91), R^(b91),R^(c91) and R^(d91) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(9A) substituents;

or, any R^(c91) and R^(d91), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(9A) substituents;

each R^(e91) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f91) and R^(g91) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h91) and R^(i91) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j91) and R^(k91) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j91) and R^(k91) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(9A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a92), SR^(a92),NHOR^(a92), C(O)R^(b92), C(O)NR⁹²R^(d92), C(O)NR^(c92)(OR^(a92)),C(O)OR^(a92), OC(O)R^(b92), OC(O)NR^(c92)R^(d92), NR^(c92)R^(d92),NR^(c92)NR^(c92)R^(d92), NR^(c92)C(O)R^(b92), NR^(c92)C(O)OR^(a92),NR^(c92)C(O)NR^(c92)R^(d92), C(═NR^(e92))R^(b92), C(═NOH)R^(b92),C(═NCN)R^(b92), C(═NR^(e92))NR^(c92)R^(d92),NR^(c92)C(═NR^(e92))NR^(c92)R^(d92), NR^(c92)C(═NOH)NR^(c92)R^(d92),NR^(c92)C(═NCN)NR^(c92)R^(d92), NR^(c92)C(═NR^(e92))R^(b92),NR^(c92)S(O)NR^(c92)R^(d92), NR^(c92)S(O)R^(b92), NR^(c92)S(O)₂R^(b92),NR^(c92)S(O)(═NR^(e92))R^(b92), NR^(c92)S(O)₂NR^(c92)R^(d92),S(O)R^(b92), S(O)NR^(c92)R^(d92), S(O)₂R^(b92), S(O)₂NR^(c92)R^(d92),S(O)(═NR^(e92))R^(b92), OS(O)(═NR^(e92))R^(b92), OS(O)₂R^(b92), SF₅,P(O)R^(f92)R^(g92), OP(O)(OR^(h92))(OR^(i92)), P(O)(OR^(h92))(OR^(i92)),and BR^(j92)R^(k92), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(9A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a92), R^(b92), R^(c92), and R^(d92) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a92), R^(b92), R^(c92) and R^(d92) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

or, any R^(c92) and R^(d92), attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroarylgroup or a 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl group or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e92) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f92) and R^(g92) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h92) and R⁹² is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

each R^(j92) and R^(k92) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j92) and R^(k92) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b11)N, C(O)NR^(c10N)R^(d10N),C(O)OR^(a10N), C(═NR^(e10N))R^(b10N) C(═NR^(e10N))NR^(c10N)R^(d10N),C(═NCN)NR^(c10N)R^(d10N), C(═NOR^(a10N))NR^(c10N), S(O)₂R^(b10N),S(O)(═NR^(c10N))R^(d10N), and S(O)₂NR^(c10N)R^(d10N), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(10NA) substituents;

each R^(a10N), R^(b10N), R^(c10N), and R^(d10N) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a10N), R^(b11N),R^(c10N), and R^(d10N) are each optionally substituted with 1, 2, 3, 4,5, 6, 7, or 8 independently selected R^(10NA) substituents;

or, any R^(c10N) and R^(d10N), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-10 memberedheteroaryl group or a 4-10 membered heterocycloalkyl group, wherein the5-10 membered heteroaryl group or 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(10NA) substituents;

each R^(e10N) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;each R^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a10N2), SR^(a10N2),NHOR^(a10N2), C(O)R^(b10N2), C(O)NR^(c10N2)R^(d11N2),C(O)NR^(c10N2)(OR^(a10N2)), C(O)OR^(a10N2), OC(O)R^(b10N2),OC(O)NR^(c10N2)R^(d10N2), NR^(c10N2)R^(d10N2),NR^(c10N2)NR^(c10N2)R^(d10N2), NR^(c10N2)C(O)R^(b10N2),NR^(c10N2)C(O)OR^(a10N2), NR^(c10N2)C(O)NR^(c10N2)R^(d10N2),C(═NR^(e10N2))R^(b10N2), C(═NOH)R^(b10N2), C(═NCN)R^(b10N2),C(═NR^(e10N2))NR^(c10N2)R^(d10N2),NR^(c10N2)C(═NR^(e10N2))NR^(c10N2)R^(d10N2),NR^(c10N2)C(═NOH)NR^(c10N2)R^(d10N2),NR^(c10N2)C(═NCN)NR^(c10N2)R^(d10N2), NR^(c10N2)C(═NR^(e10N2))R^(b10N2),NR^(c10N2)S(O)NR^(c10N2)R^(d10N2), NR^(c10N2)S(O)R^(b10N2),NR^(c10N2)S(O)₂R^(b10N2), NR^(c10N2)S(O)(═NR^(e10N2))R^(b10N2),NR^(c10N2)S(O)₂NR^(c10N2)R^(d10N2), S(O)R^(b10N2),S(O)NR^(c10N2)R^(d10N2), S(O)₂R^(b10N2), S(O)₂NR^(c10N2)R^(d10N2),S(O)(═NR^(e10N2))R^(b10N2), OS(O)(═NR^(e10N2))R^(b10N2),OS(O)₂R^(b10N2), SF₅, P(O)R^(f10N2)R^(g10N2),OP(O)(OR^(h10N2))(OR^(i10N2)), P(O)(OR^(h10N2))(OR^(i10N2)), andBR^(j10N2)R^(k10N2), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(10NA) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(a10N2), R^(b10N2), R^(c10N2), and R^(d10N2) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a10N2), R^(b10N) 2, R^(c10N2) andR^(d10N2) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents;

or, any R^(c10N2) and R^(d10N2), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-6 memberedheteroaryl group or a 4-7 membered heterocycloalkyl group, wherein the5-6 membered heteroaryl group or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents; each R^(e10N2) is independently selected from H, OH, CN,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,and C₂₋₆ alkynyl;

each R^(f10N2) and R^(g10N2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h10N2) and R^(i10N2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R^(j10N2) and R^(k10N2) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j10N2) and R^(k10N2) attached to the same B atom, togetherwith the B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R¹⁰ is independently selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a101), SR^(a101), NHOR^(a10), C(O)R^(b101),C(O)NR^(c101)R^(d101), C(O)NR^(c101)(OR^(a101)), C(O)OR^(a101),OC(O)R^(b101), OC(O)NR^(c101)R^(d101), NR^(c101)R^(d101),NR^(c101)NR^(c101)R^(d101), NR^(c101)C(O)R^(b101),NR^(c101)C(O)OR^(a101), NR^(c101)C(O)NR^(c101)R^(d101),C(═NR^(e101))R^(b101), C(═NOH)R^(b101), C(═NCN)R^(b101),C(═NR^(e101))NR^(c101)R^(d101) NR^(c101)C(═NR^(e101))NR^(c101)R^(d101),NR^(c101)C(═NOH)NR^(c101)R^(d101), NR^(c101)C(═NCN)NR^(c101)R^(d01),NR^(c101)C(═NR^(e101))R^(c101), NR^(c101)S(O)NR^(c101)R^(d101),NR^(c101)S(O)R¹⁰¹, NR^(c101)S(O)₂R^(b101),NR^(c101)S(O)(═NR^(e101))R^(b101), NR^(c101)S(O)₂NR^(c101)R^(d101)S(O)R^(b101), S(O)NR^(c101)R^(d101), S(O)₂R¹⁰¹, S(O)₂NR^(c101)R^(d101),S(O)(═NR^(e101))R^(b101), OS(O)(═NR^(e101))R^(b101), OS(O)₂R^(b101),SF₅, P(O)R^(f101)R^(g101), OP(O)(OR^(h101))(OR^(i101)),P(O)(OR^(h101))(OR^(i101)), and BR^(j101)R^(k101), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹⁰ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(10A) substituents;

each R^(a101), R^(b101), R^(c101), and R^(d101) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a101), R^(b101),R^(c101) and R^(d101) are each optionally substituted with 1, 2, 3, 4,5, 6, 7, or 8 independently selected R^(10A) substituents;

or, any R^(c101) and R^(db01), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-10 memberedheteroaryl group or a 4-10 membered heterocycloalkyl group, wherein the5-10 membered heteroaryl group or 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(10A) substituents;

each R^(e101) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f101) and R^(g101) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h101) and R^(i101) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j101) and R^(k101) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j101) and R^(k101) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(10A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a102), SR^(a102),NHOR^(a102), C(O)R^(b102), C(O)NR^(c102)R^(d102),C(O)NR^(c102)(OR^(a102)), C(O)OR^(a102), OC(O)R^(b102),OC(O)NR^(c102)R^(d102), NR^(c102)R^(d102), NR^(c102)NR^(c102)R^(d102),NR^(c102)C(O)R^(b102), NR^(c102)C(O)OR^(a102),NR^(c102)C(O)NR^(c102)R^(d102), C(═NR^(e102))R^(b102), C(═NOH)R^(b102),C(═NCN)R^(b1002), C(═NR^(e102))NR^(c102)R^(d102),NR^(c102)C(═NR^(e102))NR^(e102)R^(d102), NR^(c102)C(═NOH)NR¹⁰²R^(d102),NR^(c102)C(═NCN)NR^(c102)R^(d102), NR^(c102)C(═NR^(e102))R^(b102),NR^(c102)S(O)NRC^(c102)R^(d102), NR^(c102)S(O)R^(b102),NR^(c102)S(O)₂R^(b102), NR^(c102)S(O)(═NR^(c102))R^(b102),NR^(c102)S(O)₂NR^(c102)R^(d102), S(O)R^(b102), S(O)NR^(c102)R^(d102),S(O)₂R^(b102), S(O)₂NR^(c102)R^(d102), S(O)(═NR^(e102))R^(b102),OS(O)(═NR^(e102))R^(b102), OS(O)₂R^(b102), SF₅, P(O)R^(f102)R^(g102),OP(O)(OR^(h102))(OR^(i102)), P(O)(OR^(h102))(OR^(i102)), andBR^(j102)R^(k102), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(10A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a102), R^(b102), R^(c102), and R^(d102) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a102), R^(b102), R^(c102) andR^(d102) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents;

or, any R^(c102) and R^(d102), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-6 memberedheteroaryl group or a 4-7 membered heterocycloalkyl group, wherein the5-6 membered heteroaryl group or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e102) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f102) and R^(g102) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h102) and R^(i102) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

each R^(j102) and R^(k102) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j102) and R^(k102) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

R^(11N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b11N), C(O)NR^(c11N)R^(d11)N,C(O)OR^(a11N), C(═NR^(e11N))R^(b11N), C(═NR^(e11N))NR^(c11N)R^(d11N),C(═NCN)NR^(c11N)R^(d11N), C(═NOR^(a11N))NR^(c11N), S(O)₂R^(b11N),S(O)(═NR^(c11N))R^(d11N), and S(O)₂NR^(c11N)R^(d11N), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(11N) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(11NA) substituents;

each R^(a11N), R^(b1N), R^(c1N), and R^(d11N) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a11N), R^(b11N),R^(c11N), and R^(d11N) are each optionally substituted with 1, 2, 3, 4,5, 6, 7, or 8 independently selected R^(11NA) substituents;

or, any R^(c11N) and R^(d11N), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-10 memberedheteroaryl group or a 4-10 membered heterocycloalkyl group, wherein the5-10 membered heteroaryl group or 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(11NA) substituents;

each R^(e11N) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(11NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a11N2), SR^(a11N2),NHOR^(a11N2), C(O)R^(b11N2)C(O)NR^(c11N2)R^(d11N2),C(O)NR^(c11N2)(OR^(a11N2)), C(O)OR^(a11N2), OC(O)R^(b11N2),OC(O)NR^(c11N2)R^(d11N2), NR^(c11N2)R^(d11N2),NR^(c11N2)NR^(c11N2)R^(d11N2), NR^(c11N2)C(O)R^(b11N2),NR^(c11N2)C(O)OR^(a11N2), NR^(c11N2)C(O)NR^(c11N2)R^(d11N2),C(═NR^(e11N2))R^(b11N2), C(═NOH)R^(b11N2), C(═NCN)R^(b11N2),C(═NR^(e11N2))NR^(c11N2)R^(d11N2),NR^(c11N2)C(═NR^(e11N2))NR^(c11N2)R^(d11N2),NR^(c11N2)C(═NOH)NR^(c11N2)R^(d11N2),NR^(c11N2)C(═NCN)NR^(c11N2)R^(d11N2), NR^(c11N2)C(═NR^(e11N2))R^(b11N2),NR^(c11N2)S(O)NR^(c11N2)R^(d11N2), NR^(c11N2)S(O)R^(b11N2),NR^(c11N2)S(O)₂R^(b11N2), NR^(c11N2)S(O)(═NR^(e11N2))R^(b11N2),NR^(c11N2)S(O)₂NR^(c11N2)R^(d11N2), S(O)R^(b11N2),S(O)NR^(c11N2)R^(d11N2), S(O)₂R^(b11N2), S(O)₂NR^(c11N2)R^(d111N2),S(O)(═NR^(e11N2))R^(b11N2), OS(O)(═NR^(e11N2))R^(b11N2),OS(O)₂R^(b11N2), SF₅, P(O)R^(f11N2)R^(g11N2),OP(O)(OR^(h11N2))(OR^(c11N2)), P(O)(OR^(h11N2))(OR^(i11N2)), andBR^(j11N2)R^(k11N2), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(11NA) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(a11N2), R^(b11N2), R^(c11N2), and R^(d11N2) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a11N2), R^(b11N2), R^(c11N2) andR^(d11N2) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents;

or, any R^(c11N2) and R^(d11N2), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-6 memberedheteroaryl group or a 4-7 membered heterocycloalkyl group, wherein the5-6 membered heteroaryl group or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e11N2) is independently selected from H, OH, CN, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆alkynyl;

each R^(f11N2) and R^(g11N2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h11N2) and R^(i11N2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R^(j11N2) and R^(k11N2) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j11N2) and R^(k11N2) attached to the same B atom, togetherwith the B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R¹¹ is independently selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a111), SR^(a11), NHOR^(a111), C(O)R^(b111),C(O)NR^(c11)R^(d111), C(O)NR^(c111)(OR^(a11)), C(O)OR^(a11),OC(O)R^(b111), OC(O)NR^(c111)R^(d111), NR^(c111)R^(d111),NR^(c111)NR^(c111)R^(d111), NR^(c111)C(O)R^(b111),NR^(c111)C(O)OR^(a111), NR^(c111)C(O)NR^(c111)R^(d111),C(═NR^(e111))R^(b111), C(═NOH)R^(b111), C(═NCN)R^(b111),C(═NR^(e111))NR^(c111)R^(d111), NR^(c111)C(═NR^(e111))NR^(c111)R^(d111),NR^(c111)C(═NOH)NR^(c111)R^(d111), NR^(c111)C(═NCN)NR^(c111)R^(d111),NR^(c111)C(═NR^(e111))R^(b11), NR^(c111)S(O)NR^(c111)R^(d111),NR^(c111)S(O)R^(b111), NR^(c111)S(O)₂R^(b111),NR^(c111)S(O)(═NR^(e11))R^(b111), NR^(c111)S(O)₂NR^(c111)R^(d111),S(O)R^(b111), S(O)NR^(c11)R^(d11), S(O)₂R^(b111),S(O)₂NR^(c111)R^(d111), S(O)(═NR^(e111))R^(b11),OS(O)(═NR^(e111))R^(b111), OS(O)₂R^(b111), SF₅, P(O)R^(f111)R^(g111),OP(O)(OR^(h111))(OR^(i111)), P(O)(OR^(h111))(OR^(i111)), andBR^(j111)R^(k111), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R¹¹ are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(11A)substituents;

each R^(a111), R^(b111), R^(c111), and R^(d111) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(c111), R^(b111),R^(c111) and R^(d111) are each optionally substituted with 1, 2, 3, 4,5, 6, 7, or 8 independently selected R^(11A) substituents;

or, any R^(c111) and R^(d111), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-10 memberedheteroaryl group or a 4-10 membered heterocycloalkyl group, wherein the5-10 membered heteroaryl group or 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(11A) substituents;

each R^(e111) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f111) and R^(g111) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h111) and R^(i111) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j111) and R^(k111) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j111) and R^(k111) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl; and

each R^(11A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a112), SR^(a112),NHOR^(a112), C(O)R^(b112), C(O)NR^(c112)R^(d112)C(O)NR^(c112)(OR^(a112)), C(O)OR^(a112), OC(O)R^(b112),OC(O)NR^(c112)R^(d112), NR^(c112)R^(d112), NR^(c11)2NR^(c112)R^(d112),NR^(c112)C(O)R^(b112), NR^(c112)C(O)OR^(a112),NR^(c112)C(O)NR^(c112)R^(d112), C(═NR^(e112))R^(b112), C(═NOH)R^(b112),C(═NCN)R^(b112), C(═NR^(e112))NR^(c112)R^(d112),NR^(c112)C(═NR^(e112))NR^(c112)R^(d112),NR^(c112)C(═NOH)NR^(c112)R^(d112), NR^(c112)C(═NCN)NR^(c112)R^(d112),NR^(c112)C(═NR^(e112))R^(b112), NR^(c112)S(O)NR^(c112)R^(d12),NR^(c112)S(O)R^(b112), NR^(c112)S(O)₂R^(b112),NR^(c112)S(O)(═NR^(e112))R^(b112), NR^(c112)S(O)₂NR^(c112)R^(d112),S(O)R^(b12), S(O)NR^(c112)R^(d112), S(O)₂R^(b112),S(O)₂NR^(c112)R^(d112), S(O)(═NR^(e12))R^(b112),OS(O)(═NR^(e112))R^(b12), OS(O)₂R^(b112), SF₅, P(O)R^(f112)R^(g112),OP(O)(OR^(h112))(OR^(i112)), P(O)(OR^(h112))(OR^(i112)), andBR^(j112)R^(k112), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(11A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a112), R^(b112), R^(c112), and R^(d112) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a12), R^(b112), R^(c12) and R^(d112)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(M) substituents;

or, any R^(c112) and R^(d112), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-6 memberedheteroaryl group or a 4-7 membered heterocycloalkyl group, wherein the5-6 membered heteroaryl group or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e112) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f112) and R^(g112) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h112) and R^(i112) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

each R^(j112) and R^(k112) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j112) and R^(k112) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl.

In some embodiments:

each bond symbol represented by

is independently a single or double bond;

R¹ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a1), SR^(a1),NHOR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)NR^(c1)(OR^(a1)),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NRlC(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NOH)R^(b1), C(═NCN)R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NOH)NR^(c1)R^(d1), NR^(c1)C(═NCN)NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))R^(b1), NR^(c1)S(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)(═NR^(e1))R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),S(O)₂NR^(c1)R^(d1), S(O)(═NR^(e1))R^(b1), OS(O)(═NR^(e1))R^(b1),OS(O)₂R^(b1), SF₅, P(O)R^(f1)R^(g1), OP(O)(OR^(h1))(OR^(i1)),P(O)(OR^(h1))(OR^(i1)), and BR^(j1)R^(k1), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(1A) substituents;

each R^(a1), R^(b1), R^(c)d, and R^(d1) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a1), R^(b1), R^(c1)and R^(d1) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or8 independently selected R^(1A) substituents;

or, any R^(c1) and R^(d1), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(1A) substituents;

each R^(e1) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f1) and R^(g1) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h1) and R^(i1) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j1) and R^(k1) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j1) and R^(k1) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(1A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a11),SR^(a11), NHOR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11),C(O)NR^(c11)(OR^(a11)), C(O)OR^(a11), OC(O)R^(b11),OC(O)NR^(c11)R^(d11), NR^(c11)R^(d11), NR^(c11)NR^(c11)R^(d11),NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11), NR^(c11)C(O)NR^(c11)R^(d1),C(═NR^(e11))R^(b11), C(═NOH)R^(b1), C(═NCN)R^(b11),C(═NR^(e11))NR^(c11)R^(d11), NR^(c11)C(═NR^(e11))NR^(c11)R^(d11),NR^(c11)C(═NOH)NR^(c11)R^(d11), NR^(c11)C(═NCN)NR^(c11)R^(d11),NR^(c11)C(═NR^(e11))R^(b111), NR^(c11)S(O)NR^(c11)R^(d11),NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11),NR^(c11)S(O)(═NR^(e11))R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11), S(O)₂NR^(c11)R^(d11),S(O)(═NR^(e11))R^(b11), OS(O)(═NR^(e11))R^(b11), OS(O)₂R^(b11), SF₅,P(O)R^(f11)R^(g11), OP(O)(OR^(h11))(OR^(i11)), P(O)(OR^(h11))(OR^(i11)),and BR^(j11)R^(k11), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆-C₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(1A) are each optionally substitutedwith 1, 2, 3 or 4 independently selected R^(M) substituents;

each R^(a11), R^(b11), R^(c11), and R^(d11) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of Rail, R^(b11), R^(c11)and R^(d11) are each optionally substituted with 1, 2, 3 or 4independently selected R^(M) substituents;

or, any R^(c11) and R^(d11), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e11) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f11) and R^(g11) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆-C₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h11) and R^(g11) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j11) and R^(k11) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy; or any R^(j11) and R^(k11) attached to the same Batom, together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(M) is independently selected from D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃alkylcarbonyloxy, aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy, di(C₁₋₃alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino;

X² is N or CR²;

R² is selected from H, D, halo, CN, OH, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₇ cycloalkyl;

X⁴ is N or CR⁴;

X⁵ is N or CR⁵;

R³, R⁴ and R⁵ are each independently selected from H, D, halo, CN, OH,NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₆alkoxy-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, and C(O)NR^(a3)R^(b3);

each R^(a3) and R^(b3) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a3) and R^(b3) are eachoptionally substituted with 1, 2, 3 or 4 independently selected R^(M)substituents;

or, any R^(a3) and R^(b3), attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroarylgroup or a 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl group or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

X⁶ is N or CR⁶;

R⁶ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a6), SR^(a6),NHOR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)NR⁶(OR^(a6)), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6),C(═NR^(e6))R^(b6), C(═NOH)R^(b6), C(═NCN)R^(b6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),NR⁶C(═NOH)NR^(c6)R^(d6), NR⁶C(═NCN)NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))R^(b6), NR^(c6)S(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)(═NR^(e6))R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),S(O)₂NR^(c6)R^(d6), S(O)(═NR^(e6))R^(b6), OS(O)(═NR^(e6))R^(b6),OS(O)₂R^(b6), SF₅, P(O)R^(f6)R^(g6), OP(O)(OR^(h6))(OR^(i6)),P(O)(OR^(h6))(OR^(i6)), and BR^(j6)R^(k6), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁶ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(6A) substituents;

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a6), R^(b6), R^(c6)and R^(d6) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or8 independently selected R^(6A) substituents;

or, any R^(c6) and R^(d6), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(6A) substituents; each R^(e6) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f6) and R^(g6) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h6) and R^(i6) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j6) and R^(k6) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j6) and R^(k6) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(6A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆-C₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a61),SR^(a61), NHOR^(a61), C(O)R^(b61)C(O)NR^(c61)R^(d61),C(O)NR^(c61)(OR^(a61)), C(O)OR^(a61), OC(O)R^(b61),OC(O)NR^(c61)R^(d61), NR^(c61)R^(d61), NR^(c61)NR^(c61)R^(d61),NR^(c61)C(O)R^(b61), NR^(c61)C(O)OR^(a61), NR^(c61)C(O)NR^(c61)R^(d61),C(═NR^(e61))R^(b61), C(═NOH)R^(b61), C(═NCN)R^(b61),C(═NR^(e61))NR^(c61)R^(d61), NR^(c61)C(═NR^(e61))NR^(c61)R^(d61),NR^(c61)C(═NOH)NR^(c61)R^(d61), NR^(c61)C(═NCN)NR^(c61)R^(d61),NR^(c61)C(═NR^(e61))R^(b61), NR^(c61)S(O)NR^(c61)R^(d61),NR^(c61)S(O)R^(b61), NR^(c61)S(O)₂R^(b61),NR^(c61)S(O)(═NR^(e61))R^(b61), NR^(c61)S(O)₂NR^(c61)R^(d61),S(O)R^(b61), S(O)NR^(c61)R^(d61), S(O)₂R^(b61), S(O)₂NR^(c61)R^(d61),S(O)(═NR^(e61))R^(b61), OS(O)(═NR^(e61))R^(b61), OS(O)₂R^(b61), SF₅,P(O)R^(f61)R^(g61), OP(O)(OR^(h61))(OR^(i61)), P(O)(OR^(h61))(OR^(i61))and BR^(j61)R^(k61), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(6A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a61), R^(b61), R^(c61), and R^(d61) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a61), R^(b61),R^(c61) and R^(d61) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents;

or, any R^(c61) and R^(d61), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e61) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f61) and R^(g61) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h61) and R^(i61) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j61) and R^(k61) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j61) and R^(k61) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

X⁷ is N, CH, or C;

X⁸ is N, CH, or C;

X⁹ is N, NR⁹N, O, S, S(O), S(O)₂, CR⁹, or C(R⁹)₂;

X¹⁰ is N, NR^(10N), O, S, CR¹⁰, or C(R¹⁰)₂;

X¹¹ is N, NR^(11N), O, S, CR^(u), or C(R¹¹)₂;

wherein no more than three of X⁴, X⁵, X⁶, X⁷, and X⁸ are simultaneouslyN; and

at least two of X⁷, X⁸, X⁹, X¹⁰, and X¹¹ are independently selected fromC, CH, CR⁹, C(R⁹)₂, CR¹⁰, C(R¹⁰)₂, C^(R11), and C(R¹¹)₂; and

no two adjacent members of X⁹, X¹⁰, and X¹¹ are simultaneously O, S,S(O), or S(O)₂;

provided that (a) when X⁷ is N, then X⁸ is C; or (b) when X⁷ is C, thenX⁸ is N;

R^(9N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆-C₁₀ aryl, C₃ to cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆-C₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b9N), C(O)NR^(9N)R^(d9)N,C(O)OR^(a9N), C(═NR^(e9N))R^(b9N)C(═NR^(e9)N)NR^(c9)NR^(d9)N,C(═NCN)NR^(c9N)R^(d9)N, C(═NOR^(a9)N)NR^(c9N), S(O)₂R^(b9N),S(O)(═NR⁹N)R^(d9)N and S(O)₂NR^(9N)R^(d9N), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(9N) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(9NA) substituents;

each R^(a9N), R^(b9N), R^(c9N), and R^(d9N) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆-C₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a9N), R^(b9N),R^(c9N), and R^(d9N) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(9NA) substituents;

or, any R^(c9N) and R^(d9N), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(9NA) substituents;

each R^(e9N) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(9NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a9N2), SR^(a9N2),NHOR^(a9N2), C(O)R^(b9N2), C(O)NR^(9N2)R^(d9N2),C(O)NR^(c9N2)(OR^(a9N2)), C(O)OR^(a9N2), OC(O)R^(b9N2),OC(O)NR^(c9N2)R^(d9N2), NR^(c9N2)R^(d9N2), NR^(c9N2)NR^(c9N2)R^(d9N2),NR^(c9N2)C(O)R^(b9N2), NR^(c9N2)C(O)OR^(a9N2),NR^(c9N2)C(O)NR^(c9N2)R^(d9N2), C(═NR^(e9N2))R^(b9N2), C(═NOH)R^(b9N2),C(═NCN)R^(b9N2), C(═NR^(e9N2))NR^(c9N2)R^(d9N2),NR^(c9N2)C(═NR^(e9N2))NR^(c9N2)R^(d9N2),NR^(c9N2)C(═NOH)NR^(c9N2)R^(d9N2), NR^(c9N2)C(═NCN)NR^(c9N2)R^(d9N2),NR^(c9N2)C(═NR^(e9N2))R^(b9N2), NR^(c9N2)S(O)NR^(c9N2)R^(d9N2),NR^(c9N2)S(O)R^(b9N2), NR^(c9N2)S(O)₂R^(b9N2),NR^(c9N2)S(O)(═NR^(e9N2))R^(b9N2), NR^(c9N2)S(O)₂NR^(c9N2)R^(d9N2),S(O)R^(b9N2), S(O)NR^(c9N2)R^(d9N2), S(O)₂R^(b9N2),S(O)₂NR^(c9N2)R^(d9N2), S(O)(═NR^(e9N2))R^(b9N2),OS(O)(═NR^(e9N2))R^(b9N2), OS(O)₂R^(b9N2), SF₅, P(O)R^(f9N2)R^(g9N2),OP(O)(OR^(h9N2))(OR^(i9N2)), P(O)(OR^(h9N2))(OR^(i9N2)), andBR^(j9N2)R^(k9N2), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(9NA) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a9N2), R^(b9N2), R^(c9N2), and R^(d9N2) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a9N2), R^(b9N2), R^(c9N2) andR^(d9N2) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents;

or, any R^(c9N2) and R^(d9N2), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-6 memberedheteroaryl group or a 4-7 membered heterocycloalkyl group, wherein the5-6 membered heteroaryl group or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e9N2) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f9N2) and R^(g9N2) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h9N2) and R^(i9N2) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

each R^(j9N2) and R^(k9N2) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j9N2) and R^(k9N2) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

R⁹ is selected from H, D, halo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a91),SR^(a91), NHOR^(a91), C(O)R^(b91), C(O)NR^(c91)R^(d91),C(O)NR^(c91)(OR^(a91)), C(O)OR^(a91), OC(O)R^(b91),OC(O)NR^(c91)R^(d91), NR^(c91)R^(d91), NR^(c91)NR^(c91)R^(d91),NR^(c91)C(O)R^(b91), NR^(c91)C(O)OR^(a91), NR^(c91)C(O)NR^(c91)R^(d91),C(═NR^(e91))R^(b91), C(═NOH)R^(b91), C(═NCN)R^(b91),C(═NR^(e91))NR^(c91)R^(d91), NR^(c91)C(═NR^(e91))NR^(c91)R^(d91),NR^(c91)C(═NOH)NR^(c91)R^(d91), NR^(c91)C(═NCN)NR^(c91)R^(d91),NR^(c91)C(═NR^(e91))R^(b91), NR^(c91)S(O)NR^(c91)R^(d91),NR^(c91)S(O)R^(b91), NR^(c91)S(O)₂R^(b91),NR^(c91)S(O)(═NR^(e91))R^(b91), NR^(c91)S(O)₂NR^(c91)R^(d91),S(O)R^(b91), S(O)NR^(c91)R^(d91), S(O)₂R^(b91), S(O)₂NR^(c91)R^(d91),S(O)(═NR^(e91))R^(b91), OS(O)(═NR^(e91))R^(b91), OS(O)₂R^(b91), SF₅,P(O)R^(f91)R^(g91), OP(O)(OR^(h91))(OR^(i91)), P(O)(OR^(h91))(OR^(i91)),and BR^(j91)R^(k91), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆-C₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁹ are each optionally substituted with1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(9A) substituents;

or, alternatively, two R⁹ groups together form an oxo group;

each R^(a91), R^(b91), R^(c91), and R^(d91) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a91), R^(b91),R^(c91) and R^(d91) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(9A) substituents;

or, any R^(c91) and R^(d91), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(9A) substituents; each R^(e91) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f9) and R^(g91) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h91) and R^(i91) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C_₆alkyl-;

each R^(j91) and R^(k91) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j91) and R^(k91) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(9A) is independently selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a92), SR^(a92),NHOR^(a92), C(O)R^(b92), C(O)NR^(c92)R^(d92), C(O)NR^(c92)(OR^(a92)),C(O)OR^(a92), OC(O)R^(b92), OC(O)NR^(c92)R^(d92), NR^(c92)R^(d92),NR^(c92)NR^(c92)R^(d92), NR^(c92)C(O)R^(b92), NR^(c92)C(O)OR^(a92),NR^(c92)C(O)NR^(c92)R^(d92), C(═NR^(e92))R^(b92), C(═NOH)R^(b92),C(═NCN)R^(b92), C(═NR^(e92))NR^(c92)R^(d92),NR^(c92)C(═NR^(e92))NR^(c92)R^(d92), NR^(c92)C(═NOH)NR^(c92)R^(d92),NR^(c92)C(═NCN)NR^(c92)R^(d92), NR^(c92)C(═NR^(e92))R^(b92),NR^(c92)S(O)NR^(c92)R^(d92), NR^(c92)S(O)R^(b92), NR^(c92)S(O)₂R^(b92),NR^(c92)S(O)(═NR^(e92))R^(b92), NR^(c92)S(O)₂NR^(c92)R^(d92),S(O)R^(b92), S(O)NR^(c92)R^(d92), S(O)₂R^(b92), S(O)₂NR^(c92)R^(d92),S(O)(═NR^(e92))R^(b92), OS(O)(═NR^(e92))R^(b92), OS(O)₂R^(b92), SF₅,P(O)R^(f92)R^(g92), OP(O)(OR^(h92))(OR⁹²), P(O)(OR^(h92))(OR^(i92)), andBR^(j92)R^(k92), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(9A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a92), R^(b92), R^(c92), and R^(d92) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a92), R^(b92), R^(c92) and R^(d92) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

or, any R^(c92) and R^(d92), attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroarylgroup or a 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl group or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e92) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f92) and R^(g92) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h92) and R^(i92) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

each R^(j92) and R^(k92) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy; or any R^(j92) and R^(k92) attached to the same Batom, together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b1)N, C(O)NR^(c10N)R^(d10N),C(O)OR^(a10N), C(═NR^(e10N))R^(b10N), C(═NR^(e10N))NR^(c10N)R^(d10N),C(═NCN)NR^(c10N)R^(d10N), C(═NOR^(a10N))NR^(c10N), S(O)₂R^(b10N),S(O)(═NR^(c10N))R^(d11)N, and S(O)₂NR^(c10N)R^(d10N), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(10NA) substituents;

each R^(a10N), R^(b10N), R^(c10N), and R^(d10N) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a10N), R^(b10N),R^(c10N), and R^(d10N) are each optionally substituted with 1, 2, 3, 4,5, 6, 7, or 8 independently selected R^(10NA) substituents;

or, any R^(c10N) and R^(d10N), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-10 memberedheteroaryl group or a 4-10 membered heterocycloalkyl group, wherein the5-10 membered heteroaryl group or 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(10NA) substituents;

each R^(e10N) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a10N2), SR^(a10N2),NHOR^(a10N2), C(O)R^(b10N2), C(O)NR^(c10N2)R^(d10N2),C(O)NR^(c10N2)(OR^(a10N2)), C(O)OR^(a10N2), OC(O)R^(b10N2),OC(O)NR^(c10N2)R^(d10N2), NR^(c10N2)R^(d10N2),NR^(c10N2)NR^(c10N2)R^(d10N2), NR^(c10N2)C(O)R^(b10N2),NR^(c10N2)C(O)OR^(a10N2), NR^(c10N2)C(O)NR^(c10N2)R^(d10N2),C(═NR^(e10N)2)R^(b10N2), C(═NOH)R^(b10N2), C(═NCN)R^(b10N2),C(═NR^(e10N2))NR^(c10N2)R^(d10N2),NR^(c10N2)C(═NR^(e10N2))NR^(c10N2)R^(d10N2),NR^(c10N2)C(═NOH)NR^(c10N2)R^(d10N2),NR^(c10N2)C(═NCN)NR^(c10N2)R^(d10N2), NR^(c10N2)C(═NR^(e10N2))R^(b10N2),NR^(c10N2)S(O)NR^(c10N2)R^(d10N2), NR^(c10N2)S(O)R^(b10N2),NR^(c10N2)S(O)₂R^(b10N2), NR^(c10N2)S(O)(═NR^(e10N2))R^(b10N2),NR^(c10N2)S(O)₂NR^(c10N2)R^(d10N2), S(O)R^(b10N2),S(O)NR^(c10N2)R^(d10N2), S(O)₂R^(b10N2), S(O)₂NR^(c10N2)R^(d10N2),S(O)(═NR^(e10N)2)R^(b10N2), OS(O)(═NR^(e10N)2)R^(b10N2),OS(O)₂R^(b10N2), SF₅, P(O)R^(f10N2)R^(g10N2),OP(O)(OR^(h10N2))(OR^(i10N2)), P(O)(OR^(h10N2))(OR^(i10N2)), andBR^(j10N2)R^(k10N2), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(10NA) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(a10N2), R^(b10N2), R^(c10N2), and R^(d10N2) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a10N2), R^(b11N2), R^(c10N2) andR^(d10N2) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents;

or, any R^(c10N2) and R^(d10N2), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-6 memberedheteroaryl group or a 4-7 membered heterocycloalkyl group, wherein the5-6 membered heteroaryl group or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e10N2) is independently selected from H, OH, CN, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆alkynyl;

each R^(f10N2) and R^(g10N2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h10N2) and R^(i10N2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R^(j10N2) and R^(k10N2) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j10N2) and R^(k10N2) attached to the same B atom, togetherwith the B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

R¹⁰ is selected from H, D, halo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a101),SR^(a101), NHOR^(a101), C(O)R^(b101), C(O)NR^(c101)R^(d101),C(O)NR^(c101)(OR^(a101)), C(O)OR^(a101), OC(O)R^(b101),OC(O)NR^(c101)R^(d101), NR^(c101)R^(d101), NR^(c101)NR^(c101)R^(d101),NR^(c101)C(O)R^(b101), NR^(c101)C(O)O^(Ra101),NR^(c101)C(O)NR^(c101)R^(d101), C(═NR^(e101))R^(c101), C(═NOH)R^(b101),C(═NCN)R^(b101), C(═NR^(e101))NR^(c101)R^(d101),NR^(c101)C(═NR^(c101))NR^(c101)R^(d101),NR^(c101)C(═NOH)NR^(c101)R^(d101), NR^(c101)C(═NCN)NR^(c101)R^(d101),NR^(c101)C(═NR^(c101))R^(b101), NR^(c101)S(O)NR^(c101)R^(d101),NR^(c101)S(O)R^(b101), NR^(c101)S(O)₂R^(b101),NR^(c101)S(O)(═NR^(e101))R^(b101), NR^(c101)S(O)₂NR^(c101)R^(d101),S(O)R^(b101), S(O)NR^(c101)R^(d101), S(O)₂R^(b101),S(O)₂NR^(c101)R^(d101), S(O)(═NR^(e101))R^(b101),OS(O)(═NR^(e101))R^(b101), OS(O)₂R^(b101), SF₅, P(O)R^(f101)R^(g101),OP(O)(OR^(h101))(OR^(i101)), P(O)(OR^(h101))(OR^(i101)), andBR^(j101)R^(k101), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R¹⁰ are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(10A)substituents;

each R^(a101), R^(b101), R^(c101), and R^(d101) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a101), R^(b101),R^(c101) and R^(d101) are each optionally substituted with 1, 2, 3, 4,5, 6, 7, or 8 independently selected R^(10A) substituents;

or, any R^(c101) and R^(d101), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-10 memberedheteroaryl group or a 4-10 membered heterocycloalkyl group, wherein the5-10 membered heteroaryl group or 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(10A) substituents;

each R^(e101) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f101) and R^(g101) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h101) and R^(i101) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j101) and R^(k101) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j101) and R^(k101) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

each R^(10A) is independently selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a102), SR^(a102),NHOR^(a02), C(O)R^(b102), C(O)NR^(c102)R^(d102),C(O)NR^(c102)(OR^(a102)), C(O)OR^(a102), OC(O)R^(b102),OC(O)NR^(c102)R^(d102), NR^(c102)R^(d102), NR^(c102)NR^(c102)R^(d102),NR^(c102)C(O)R^(b102), NR^(c102)C(O)OR^(a102),NR^(c102)C(O)NR^(c102)R^(d102), C(═NR^(e102))R^(b102), C(═NOH)R^(b102),C(═NCN)R^(b102), C(═NR^(e102))NR^(c102)R^(d102),NR^(c102)C(═NR^(e102))NR^(c102)R^(d102),NR^(c102)C(═NOH)NR^(c102)R^(d102), NR^(c102)C(═NCN)NR^(c102)R^(d102),NR^(c102)C(═NR^(e102))R^(b102), NR^(c102)S(O)NR^(c102)R^(d102),NR^(c102)S(O)R^(b102), NR^(c102)S(O)₂R^(b102),NR^(c102)S(O)(═NR^(e102))R^(b1002) NR^(c102)S(O)₂NR^(c102)R^(d102),S(O)R^(b102), S(O)NR^(c102)R^(d102), S(O)₂R^(b102),S(O)₂NR^(c102)R^(d102), S(O)(═NR^(b102))R^(b102),OS(O)(═NR^(e102))R^(b102), OS(O)₂R^(b102), SF₅, P(O)R^(f102)R^(g102),OP(O)(OR^(h102))(OR^(i102)), P(O)(OR^(h102))(OR^(i102)), andBR^(j102)R^(k102), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(10A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a102), R^(b102), R^(c102), and R^(d102) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a02), R^(b102), R^(c)10² andR^(d102) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents;

or, any R^(c102) and R^(d102), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-6 memberedheteroaryl group or a 4-7 membered heterocycloalkyl group, wherein the5-6 membered heteroaryl group or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e102) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f102) and R^(g102) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h102) and R^(i102) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

each R^(j102) and R^(k102) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j102) and R^(k102) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

R^(11N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b11)N, C(O)NR^(c11N)R^(d11)N,C(O)OR^(a11N), C(═NR^(e11N))R^(b11)N C(═NR^(e11N))NR^(c11N)R^(d11N),C(═NCN)NR^(c11N)R^(d11)N, C(═NOR^(a11N))NR^(c11N), S(O)₂R^(b11N),S(O)(═NR^(c11N))R^(d11N), and S(O)₂NR^(c11)NR^(d11N), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(11N) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(11NA) substituents;

each R^(a11N), R^(b11N), R^(c11N), and R^(d11N) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a11N), R^(b11)N,R^(c11N), and R^(d11N) are each optionally substituted with 1, 2, 3, 4,5, 6, 7, or 8 independently selected R^(11NA) substituents;

or, any R^(c11N) and R^(d11)N, attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-10 memberedheteroaryl group or a 4-10 membered heterocycloalkyl group, wherein the5-10 membered heteroaryl group or 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(11NA) substituents;

each R^(e11N) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(11NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a11N2), SR^(a11N2),NHOR^(a11N2), C(O)R^(b11N2), C(O)NR^(c11N2)R^(d11N2),C(O)NR^(c11N2)(OR^(a11N2)), C(O)OR^(a11N2), OC(O)R^(b11N2),OC(O)NR^(c11N2)R^(d11N2), NR^(c11N2)R^(d11N2),NR^(c11N2)NR^(c11N2)R^(d11N2), NR^(c11N2)C(O)R^(b11N2),NR^(c11N2)C(O)OR^(a11N2), NR^(c11N2)C(O)NR^(c11N2)R^(d11N2),C(═NR^(e11N2))R^(b11N2), C(═NOH)R^(b11N2), C(═NCN)R^(b11N2),C(═NR^(e11N2))NR^(c11N2)R^(d11N2),NR^(c11N2)C(═NR^(e11N2))NR^(c11N2)R^(d11N2),NR^(c11N2)C(═NOH)NR^(c11N2)R^(d11N2),NR^(c11N2)C(═NCN)NR^(c11N2)R^(d11N2), NR^(c11N2)C(═NR^(e11N2))R^(b11N2),NR^(c11N2)S(O)NR^(c11N2)R^(d11N2), NR^(c11N2)S(O)R^(b11N2),NR^(c11N2)S(O)₂R^(b11N2), NR^(c11N2)S(O)(═NR^(e11N2))R^(b11N2),NR^(c11N2)S(O)₂NR^(c11N2)R^(d11N2), S(O)R^(b11N2),S(O)NR^(c11N2)R^(d11N2), S(O)₂R^(b11N2), S(O)₂NR^(c11N2)R^(d11N2),S(O)(═NR^(e11N2))R^(b11N2), OS(O)(═NR^(e11N2))R^(b11N2),OS(O)₂R^(b11N2), SF₅, P(O)R^(f11N2)R^(g11N2),OP(O)(OR^(h11N2))(OR^(i11N2)), P(O)(OR^(h11N2))(OR^(i11N2)), andBR^(j11N2)R^(k11N2), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(11NA) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(a11N2), R^(b11N2), R^(c11N2), and R^(d11N2) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a11N2)R^(b11N2), R^(c11N2) andR^(d11N2) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents;

or, any R^(c11N2) and R^(d11N2), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-6 memberedheteroaryl group or a 4-7 membered heterocycloalkyl group, wherein the5-6 membered heteroaryl group or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e11N2) is independently selected from H, OH, CN, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆alkynyl;

each R^(f11N2) and R^(g11N2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-; each R^(h11N2) and R^(11N2) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(j11N2) and R^(k11N2) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j11N2) and R^(k11N2) attached to the same B atom, togetherwith the B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl;

R¹¹ is selected from H, D, halo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a111),SR^(a111), NHOR^(a111), C(O)R^(b11), C(O)NR^(c111)R^(d111),C(O)NR^(c111)(OR^(a111)), C(O)OR^(a111), OC(O)R^(b111),OC(O)NR^(c111)R^(d111), NR^(c111)R^(d111), NR^(c111)NR^(c111)R^(d111),NR^(c111)C(O)R^(b111), NR^(c111)C(O)OR^(a111),NR^(c111)C(O)NR^(c111)R^(d111), C(═NR^(e11))R^(b111), C(═NOH)R^(b11),C(═NCN)R^(b111), C(═NR^(e111))NR^(c11)R^(d111),NR^(c111)C(═NR^(e111))NR^(c111)R^(d111),NR^(c111)C(═NOH)NR^(c11)R^(d111), NR^(c111)C(═NCN)NR^(c111)R^(d111),NR^(c111)C(═NR^(e111))R^(b111), NR^(c111)S(O)NR^(c111)R^(d111),NR^(c111)S(O)R^(b111), NR^(c111)S(O)₂R^(b111),NR^(c111)S(O)(═NR^(e111))R^(b111), NR^(c111)S(O)₂NR^(c11)R^(d111),S(O)R^(b111), S(O)NR^(c111)R^(d111), S(O)₂R^(b111),S(O)₂NR^(c111)R^(d111), S(O)(═NR^(e111))R^(b111),OS(O)(═NR^(e111))R^(b111), OS(O)₂R^(b111), SF₅, P(O)R^(f111)R^(g111),OP(O)(OR^(h111))(OR^(i111)), P(O)(OR^(h111))(OR^(i111)), andBR^(j111)R^(k111), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R¹¹ are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(11A)substituents;

each R^(a111), R^(b111), R^(c111), and R^(d111) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a111), R^(b111),R^(c111) and R^(d111) are each optionally substituted with 1, 2, 3, 4,5, 6, 7, or 8 independently selected R^(11A) substituents;

or, any R^(c111) and R^(d111), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-10 memberedheteroaryl group or a 4-10 membered heterocycloalkyl group, wherein the5-10 membered heteroaryl group or 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(11A) substituents;

each R^(e111) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f111) and R^(g111) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered hetereocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered hetereocycloalkyl)-C₁₋₆ alkyl-;

each R^(h11) and R^(i111) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered hetereocycloalkyl)-C₁₋₆alkyl-;

each R^(j111) and R^(k111) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j111) and R^(k111) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl; and

each R^(11A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a112), SR^(a112),NHOR^(a112), C(O)R^(b112), C(O)NR^(c112)R^(d112),C(O)NR^(c112)(OR^(a112)), C(O)OR^(a112), OC(O)R^(b112),OC(O)NR^(c112)R^(d112), NR^(c112)R^(d112), NR^(c112)NR^(c112)R^(d112),NR^(c112)C(O)R^(b112), NR^(c112)C(O)OR^(a112),NR^(c112)C(O)NR^(c112)R^(d112), C(═NR^(e112))R^(b112), C(═NOH)R^(b112),C(═NCN)R^(b112), C(═NR^(e112))NR^(c112)R^(d112),NR^(c112)C(═NR^(e112))NR^(c112)R^(d112),NR^(c112)C(═NOH)NR^(c112)R^(d112), NR^(c112)C(═NCN)NR^(c112)R^(d112),NR^(c112)C(═NR^(e112))R^(b112), NR^(c112)S(O)NR^(c112)R^(d112),NR^(c112)S(O)R^(b112), NR^(c112)S(O)₂R^(b112),NR^(c112)S(O)(═NR^(e112))R^(b112), NR^(c112)S(O)₂NR^(c112)R^(d112),S(O)R^(b112), S(O)NR^(c112)R^(d112), S(O)₂R^(b112),S(O)₂NR^(c112)R^(d12), S(O)(═NR^(e112)R^(b112),OS(O)(═NR^(e112))R^(b112), OS(O)₂R^(b112), SF₅, P(O)R^(f12)R^(g12)OP(O)(OR^(h12))(OR^(i112)), P(O)(OR^(h112))(OR^(i112)) andBR^(j112)R^(k112), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(11A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a112), R^(b112), R^(c112), and R^(d112) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a112), R^(b12), R^(c112) andR^(d112) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents;

or, any R^(c112) and R^(d112), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-6 memberedheteroaryl group or a 4-7 membered heterocycloalkyl group, wherein the5-6 membered heteroaryl group or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e112) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(e112) and R^(g112) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h112) and R^(i112) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

each R^(j112) and R^(k112) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j112) and R^(k112) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered hetereocycloalkyl.

In some embodiments, R¹ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a1), SR^(a1), NHOR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)NR^(c1)(OR^(a1)), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NOH)R^(b1),C(═NCN)R^(b1), NR^(c1)C(═NOH)NR^(c1)R^(d1), NR^(c1)C(═NCN)NR^(c1)R^(d1),NR^(c1)S(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),S(O)₂NR^(c1)R^(d1), and OS(O)₂R^(b1), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹ are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(1A)substituents; and

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a1), R^(b1), R^(c1)and R^(d1) are each optionally substituted with 1, 2, 3, or 4,independently selected R^(1A) substituents.

In some embodiments, R¹ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), andS(O)₂R^(b1), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl of R¹ are each optionally substituted with 1, 2, 3, or4 independently selected R^(1A) substituents; and

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylof R^(a1), R^(b1), R^(c1) and R^(d1) are each optionally substitutedwith 1, 2, 3, or 4, independently selected R^(1A) substituents.

In some embodiments, each R^(a1), R^(b1), and R^(c1) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6 memberedheterocycloalkyl of R^(a1), R^(b1), R^(c1) and R^(d1) are eachoptionally substituted with 1 or 2 independently selected R^(1A)substituents; and

wherein each R^(d1) is independently selected from C₂₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, and 4-6 membered heterocycloalkyl, wherein the C₂₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-6 membered heterocycloalkyl of R^(d1) is optionallysubstituted with 1 or 2 independently selected R^(1A) substituents.

In some embodiments, wherein each R^(c1) is independently selected fromH, C₁₋₆ alkyl, and 4-6 membered heterocycloalkyl, wherein the C₁₋₆ alkyland 4-6 membered heterocycloalkyl of R^(c1) is optionally substitutedwith 1 or 2 independently selected R^(1A) substituents; and

wherein each R^(d1) is independently selected from C₂₋₆ alkyl, and 4-6membered heterocycloalkyl, wherein the C₂₋₆ alkyl and 4-6 memberedheterocycloalkyl of R^(d1) is optionally substituted with 1 or 2independently selected R^(1A) substituents.

In some embodiments, R¹ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), andS(O)₂R^(b1), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl of R¹ are each optionally substituted with 1, 2, 3, or4 independently selected R^(1A) substituents; and

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromC₂₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl of R^(a1),R^(b1), R^(c1) and R^(d1) are each optionally substituted with 1, 2, 3,or 4, independently selected R^(1A) substituents.

In some embodiments, R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, andC(O)NR^(c1)R^(d1), wherein the C₁₋₆ alkyl, 5-6 membered heteroaryl, and4-7 membered heterocycloalkyl are optionally substituted with 1, 2, 3,or 4 independently selected R^(1A) substituents; and

each R^(c1) and R^(d1) is independently selected from H, C₁₋₆ alkyl and4-7 membered heterocycloalkyl.

In some embodiments, R¹ is selected from H, D, C₁₋₆ alkyl, C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)NR^(c1)(OR^(a1)), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)CR^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),S(O)₂NR^(c1)R^(d1), 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, wherein the 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are optionally substituted with 1 or 2 independentlyselected R^(1A) substituents; and

each R^(a1), R^(b1), R^(c1) and R^(d1) is independently selected from H,C₂₋₆ alkyl and 4-7 membered heterocycloalkyl.

In some embodiments, R¹ is selected from H, D, C₁₋₆ alkyl, C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)NR^(c1)(OR^(a1)), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, wherein the 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are optionally substituted with 1 or 2 independentlyselected R^(1A) substituents; and

each R^(a1), R^(b1), R^(c1) and R^(d1) is independently selected fromC₂₋₆ alkyl and 4-7 membered heterocycloalkyl.

In some embodiments, R¹ is selected from H, C(O)R^(b1),C(O)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, wherein the 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are optionally substituted with 1 or 2 independentlyselected R^(1A) substituents; and

each R^(a1), R^(b1), R^(c1) and R^(d1) is independently selected fromC₂₋₆ alkyl and 4-7 membered heterocycloalkyl.

In some embodiments, R¹ is selected from H, C(O)NR^(c1)R^(d1), 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein the 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are optionallysubstituted with 1 or 2 independently selected R^(1A) substituents; and

each R^(c1) and R^(d1) is independently selected from H, C₂₋₆ alkyl and4-7 membered heterocycloalkyl.

In some embodiments, R¹ is 5-membered heteroaryl optionally substitutedwith 1 or 2 independently selected R^(1A) substituents.

In some embodiments, R¹ is 4-membered heterocycloalkyl optionallysubstituted with 1 or 2 independently selected R^(1A) substituents.

In some embodiments, R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,and C(O)NR^(c1)R^(d1) wherein the C₁₋₆ alkyl is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(1A) substituents; and

each R^(c1) and R^(d1) is independently selected from H, C₁₋₆ alkyl and4-7 membered heterocycloalkyl.

In some embodiments, R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,and C(O)NR^(c1)R^(d1), wherein the C₁₋₆ alkyl is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(1A) substituents; and

each R^(c1) and R^(d1) is independently selected from C₂₋₆ alkyl and 4-7membered heterocycloalkyl.

In some embodiments, R¹ is selected from H, D, C₁₋₆ alkyl, C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)NR^(c1)(OR^(a1)), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1).

In some embodiments, R¹ is selected from H, D, C₁₋₆ alkyl, C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)NR^(c1)(OR^(a1)), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), andNR^(c1)C(O)NR^(c1)R^(d1).

In some embodiments, R¹ is selected from H, C(O)R^(b1),C(O)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), andNR^(c1)C(O)NR^(c1)R^(d1) In some embodiments, R¹ is selected from H andC(O)NR^(c1)R^(d1).

In some embodiments, each R^(a1), R^(b1), R^(c1), and R^(d1) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl of R^(a1), R^(b1), R^(c1) and R^(d1) are eachoptionally substituted with 1 or 2 independently selected R^(1A)substituents.

In some embodiments, each R^(c1) and R^(d1) is independently selectedfrom H, C₁₋₆ alkyl, and 4-6 membered heterocycloalkyl, wherein the C₁₋₆alkyl and 4-6 membered heterocycloalkyl of R^(o1) and R^(d1) are eachoptionally substituted with 1 or 2 independently selected R^(1A)substituents.

In some embodiments, each R^(c1) and R^(d1) is independently selectedfrom H, C₁₋₆ alkyl, and 4-6 membered heterocycloalkyl.

In some embodiments, each R^(c1) and R^(d1) is independently selectedfrom C₂₋₆ alkyl, and 4-6 membered heterocycloalkyl.

In some embodiments, each R^(c1) is H; and each R^(d1) is independentlyselected from C₂₋₆ alkyl, and 4-6 membered heterocycloalkyl.

In some embodiments, each R^(c1) is H; and R^(d1) is selected fromisopropyl, and tetrahydropyranyl.

In some embodiments, R¹ is selected from H, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl and C(O)NHR^(d1), wherein the 5-6 memberedheteroaryl or 4-7 membered heterocycloalkyl is optionally substitutedwith 1 or 2 independently selected R^(1A) substituents, and whereinR^(d1) is a C₁₋₆ alkyl or 5-6 membered heterocycloalkyl.

In some embodiments, R¹ is selected from H, azetidinyl, triazolyl,pyrazolyl, thiazolyl, and C(O)NHR^(d1), wherein the azetidinyl,triazolyl, pyrazolyl, and thiazolyl are optionally substituted with 1 or2 independently selected R^(1A) substituents, and wherein R^(d1) is aC₁₋₆ alkyl or 5-6 membered heterocycloalkyl.

In some embodiments, each R^(1A) is independently selected from C₁₋₆alkyl and C(O)R^(b11), wherein each R^(b11) is independently selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₁₀ cycloalkyl, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, and C₃₋₁₀ cycloalkyl of R^(b11) are eachoptionally substituted with 1 or 2 independently selected R^(M)substituents.

In some embodiments, each R^(1A) is independently selected from C₁₋₆alkyl and C(O)R^(b1), wherein each R^(b11) is C₃₋₁₀ cycloalkyl,optionally substituted with C₁₋₆ haloalkyl.

In some embodiments, each R^(1A) is independently selected from methyland 1-(trifluoromethyl)cyclopropane-1-carbonyl.

In some embodiments, R¹ is selected from H, CF₃, and C(O)NHR^(d1),wherein R^(d1) is a C₁₋₆ alkyl or 5-6 membered heterocycloalkyl.

In some embodiments, R¹ is selected from H, CF₃, C(O)NHC(CH₃)₂, andC(O)NH-tetrahydropyran.

In some embodiments, R¹ is H.

In some embodiments, R¹ is CF₃.

In some embodiments, R¹ is 5-6 membered heteroaryl optionallysubstituted with 1 or 2 independently selected R^(1A). In someembodiments, R¹ is triazolyl optionally substituted with 1 or 2independently selected R^(1A). In some embodiments, R¹ is pyrazolyloptionally substituted with 1 or 2 independently selected R^(1A). Insome embodiments, R¹ is thiazolyl optionally substituted with 1 or 2independently selected R^(1A).

In some embodiments, R¹ is 4-7 membered heterocycloalkyl optionallysubstituted with 1 or 2 independently selected R^(1A). In someembodiments, R¹ is azetidinyl optionally substituted with 1 or 2independently selected R^(1A).

In some embodiments, R¹ is selected from H,tetrahydropyranylaminocarbonyl, isopropylaminocarbonyl,1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl,2-methylthiazol-5-yl, 3-methyl-1H-pyrazol-4-yl, 1H-pyrazol-4-yl,1H-1,2,4-triazol-1-yl, and1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)azetidin-3-yl.

In some embodiments, R¹ is selected from tetrahydropyranylaminocarbonyl,isopropylaminocarbonyl, 1-methyl-1H-pyrazol-5-yl,1-methyl-1H-pyrazol-4-yl, 2-methylthiazol-5-yl,3-methyl-1H-pyrazol-4-yl, 1H-pyrazol-4-yl, 1H-1,2,4-triazol-1-yl, and1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)azetidin-3-yl.

In some embodiments, R¹ is selected from H,tetrahydropyranylaminocarbonyl, and isopropylaminocarbonyl.

In some embodiments, R¹ is selected from tetrahydropyranylaminocarbonyland isopropylaminocarbonyl.

In some embodiments, X² is N.

In some embodiments, X² is CR².

In some embodiments, X² is CR², wherein R² is selected from H, D, halo,CN, OH, NH₂, and C₁₋₆ alkyl.

In some embodiments, X² is CH.

In some embodiments, R³ is selected from H, D, halo, CN, OH, NH₂, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R³ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R³ is selected from H, D, halo, CN, OH, NH₂, andC₁₋₆ alkyl.

In some embodiments, R³ is H.

In some embodiments, X⁴ is N.

In some embodiments, X⁴ is CR⁴.

In some embodiments, X⁴ is CR⁴, wherein R⁴ is selected from H, D, halo,CN, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, X⁴ is CR⁴, wherein R⁴ is selected from H, D, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, X⁴ is CR⁴, wherein R⁴ is selected from H, D, halo,CN, OH, NH₂, and C₁₋₆ alkyl.

In some embodiments, X⁴ is CH.

In some embodiments, X⁵ is N.

In some embodiments, X⁵ is CR⁵, wherein R⁵ is selected from H, D, halo,CN, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, X⁵ is CR⁵, wherein R⁵ is selected from H, D, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, X⁵ is CR⁵, wherein R⁵ is selected from H, D, halo,CN, OH, NH₂, and C₁₋₆ alkyl.

In some embodiments, X⁵ is CH.

In some embodiments, X⁶ is N.

In some embodiments, X⁶ is CR⁶.

In some embodiments, R⁶ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a6), SR^(a6), NHOR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)NR⁶(OR^(a6)), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6), C(═NOH)R^(b6),C(═NCN)R^(b6), NR^(c6)C(═NOH)NR^(c6)R^(d6), NR⁶C(═NCN)NR^(c6)R^(d6),NR^(c6)S(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR⁶S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),S(O)₂NR^(c6)R^(d6), and OS(O)₂R^(b6), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁶ are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(6A)substituents;

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a6), R^(b6), R^(c6)and R^(d6) are each optionally substituted with 1, 2, 3, or 4independently selected R^(6A) substituents;

each R^(6A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a61),SR^(a61), NHOR^(a61), C(O)R^(b61), C(O)NR^(c61)R^(d61),C(O)NR^(c61)(OR^(a61)), C(O)OR^(a61), OC(O)R^(b61),OC(O)NR^(c61)R^(d61), NR^(c61)R^(d61), NR^(c61)NR^(c61)R^(d61),NR^(c61)C(O)R^(b61), NR^(c61)C(O)OR^(a61), NR^(c61)C(O)NR^(c61)R^(d61),C(═NOH)R^(b61), C(═NCN)R^(b61), NR^(c61)C(═NOH)NR^(c61)R^(d61),NR^(c61)C(═NCN)NR^(c61)R^(d61), NR^(c61)S(O)NR^(c61)R^(d61),NR^(c61)S(O)R^(b61), NR^(c61)S(O)₂R^(b61), NR^(c61)S(O)₂NR^(c61)R^(d61),S(O)R^(b61), S(O)NR^(c61)R^(d61), S(O)₂R^(b61), S(O)₂NR^(c61)R^(d61),and OS(O)₂R^(b61), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(6A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; and

wherein each R^(a61), R^(b61), R^(c61), and R^(d61) is independentlyselected from H and C₁₋₆ alkyl.

In some embodiments, R⁶ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO₂, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6), andS(O)₂R^(b6), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl of R⁶ are each optionally substituted with 1, 2, 3, or4 independently selected R^(6A) substituents;

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylof R^(a6), R^(b6), R^(c6) and R^(d6) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(6A) substituents; and

each R^(6A) is selected from H, D, halo, CN, OH, NH₂, and C₁₋₆ alkyl.

In some embodiments, R⁶ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, SR^(a6), C(O)NR^(c6)R^(d6), C(O)R^(b6), and S(O)₂R^(b6),wherein the C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4independently selected R^(6A) substituents;

each R^(a6), R^(b6), R^(c6) and R^(d6) is independently selected from Hand C₁₋₆ alkyl; and

each R^(6A) is selected from H, D, halo, CN, OH, NH₂, and C₁₋₆ alkyl.

In some embodiments, R⁶ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6).

In some embodiments, R⁶ is selected from H, halo, C₁₋₆ alkyl,S(O)R^(b6), and S(O)₂R^(b6), and R^(b6) is selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, each R^(b6), R^(c6), and R^(d6) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl.

In some embodiments, R⁶ is selected from H, D, halo, C₁₋₆ alkyl,SR^(a6), C(O)R^(b6), and S(O)₂R^(b6), wherein the C₁₋₆ alkyl isoptionally substituted with 1, 2, 3, or 4 independently selected R^(6A)substituents;

each R^(a6) and R^(b6) is independently selected from H and C₁₋₆ alkyl;and

each R^(6A) is selected from H, D, halo, CN, OH, NH₂, and C₁₋₆ alkyl.

In some embodiments, R⁶ is selected from H, D, halo, methyl, C(CH₃)₂₀H,CH(CH₃)OH, C(O)CH₃, S(O)₂CH₃, and SCH₃.

In some embodiments, R⁶ is S(O)₂CH₃.

In some embodiments, R⁶ is CH(OH)—CH₂OH.

In some embodiments, R⁶ is C(CH₃)(OH)—CH₂OH.

In some embodiments, R⁶ is C(OH)(C₁-haloalkyl)-CH₂OH.

In some embodiments, R⁶ is C(OH)(S(═O)R^(b6))—CH₂OH.

In some embodiments, R⁶ is C(OH)(C₁-haloalkyl)-C(O)NH₂.

In some embodiments, R⁶ is C(O)NH₂.

In some embodiments, R⁶ is methyl.

In some embodiments, R⁶ is H.

In some embodiments, R⁶ is selected from D, halo, methyl, C(CH₃)₂OH,CH(CH₃)OH, C(O)CH₃, S(O)₂CH₃, and SCH₃.

In some embodiments, R⁶ is a C(OH)(R^(6A))₂, wherein at least one R^(6A)is C₁₋₆ haloalkyl. In some embodiments, each halogen is F. In someembodiments, the haloalkyl is optionally substituted with 1 or 2independently selected Y² substituents.

In some embodiments, each Y² is independently selected from OH, NO₂, CN,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆alkyl, HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino.

In some embodiments, at least one R^(6A) is selected from CF₃, CCl₃,CF₂H, CCl₂H, CF₂Y², CCl₂Y₂, CFH₂, CClH₂, CFHY², CClHY², CF(Y²)₂ andCCl(Y²)₂.

In some embodiments, at least one R^(6A) is selected from CF₃, CF₂H,CF₂Y², CFH₂, CFHY², and CF(Y²)₂.

In some embodiments, at least one R^(6A) is C₁₋₆ haloalkyl, wherein eachhalogen is F.

In some embodiments, at least one R^(6A) is C₁₋₆ haloalkyl, wherein eachhalogen is Cl.

In some embodiments, at least one R^(6A) is selected from CH₂F, CHF₂,CF₃, and CF₂CF₃.

In some embodiments, at least one R^(6A) is CF₃.

In some embodiments, at least one R^(6A) is CH₂F.

In some embodiments, at least one R^(6A) is CHF₂.

In some embodiments, at least one R^(6A) is CF₂CF₃.

In some embodiments, R⁶ is selected from H, methyl, and S(O)₂CH₃.

In some embodiments, X⁷ is N.

In some embodiments, X⁷ is C.

In some embodiments, X⁷ is CH.

In some embodiments, X⁸ is N.

In some embodiments, X⁸ is C.

In some embodiments, X⁸ is CH.

In some embodiments, both X⁷ and X⁸ are C.

In some embodiments, X⁷ is N and X⁸ is C.

In some embodiments, X⁷ is C and X⁸ is N.

In some embodiments, X⁹ is NR^(9N).

In some embodiments, X⁹ is N.

In some embodiments, X⁹ is O.

In some embodiments, X⁹ is S.

In some embodiments, X⁹ is S(O).

In some embodiments, X⁹ is S(O)₂.

In some embodiments, X⁹ is CR⁹.

In some embodiments, X⁹ is C(R⁹)₂.

In some embodiments, each R⁹ is independently selected from H, D, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, of R⁹ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(9A)substituents; or, alternatively, two R⁹ groups together form an oxogroup.

In some embodiments, each R⁹ is H.

In some embodiments, X⁹ is CR⁹, wherein R⁹ is selected from H, D, halo,CN, OH, NH₂, and C₁₋₆ alkyl.

In some embodiments, X⁹ is CH.

In some embodiments, X⁹ is C(O).

In some embodiments, X¹⁰ is NR^(10N).

In some embodiments, R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, C(O)R^(b10N), C(O)NR^(c10N)R^(d10N)C(O)OR^(a10N),C(═NCN)NR^(c10N)R^(d10N), C(═NOR^(a10N))NR^(c10N), S(O)₂R^(b10N),S(O)(═NR^(c10N))R^(d10N), and S(O)₂NR^(c10N)R^(d10N), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(10NA) substituents;

each R^(a10N), R^(b10N), R^(c10N), and R^(d10N) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a11N), R^(b10N),R^(c10N), and R^(d10N) are each optionally substituted with 1, 2, 3, or4 independently selected R^(10NA) substituents;

each R^(10NA) is selected from H, D, halo, CN, OH, NH₂, C₁₋₆ alkyl, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-.

In some embodiments, R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(10NA) substituents.

In some embodiments, R^(10N) is selected from C₁₋₆ alkyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-6 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₆cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl- and (4-6membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are each optionallysubstituted with 1 or 2 independently selected R^(10NA) substituents.

In some embodiments, R^(10N) is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl- of R^(10N) are eachoptionally substituted with 1 or 2 independently selected R^(10NA)substituents.

In some embodiments, R^(10N) is selected from H, C₁₋₆ alkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, and C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-.

In some embodiments, R^(10N) is C₃₋₆ cycloalkyl-C₁₋₆ alkyl-.

In some embodiments, R^(10N) is cyclopropylethyl.

In some embodiments, R^(10N) is 1-cyclopropylethyl.

In some embodiments, R^(10N) is (S)-1-cyclopropylethyl.

In some embodiments, X¹⁰ is N.

In some embodiments, X¹⁰ is O.

In some embodiments, X¹⁰ is S.

In some embodiments, X¹⁰ is CR¹¹.

In some embodiments, X¹⁰ is C(R¹⁰)₂.

In some embodiments, X¹⁰ is CR¹⁰, wherein R¹⁰ is selected from H, D,halo, oxo, CN, OH, NH₂, and C₁₋₆ alkyl.

In some embodiments, X¹⁰ is CH.

In some embodiments, X¹⁰ is C(R¹⁰)₂, wherein each R¹⁰ is independentlyselected from H, D, halo, oxo, CN, OH, NH₂, and C₁₋₆ alkyl.

In some embodiments, X¹¹ is NR¹N.

In some embodiments, X¹¹ is N.

In some embodiments, X¹¹ is O.

In some embodiments, X¹¹ is S.

In some embodiments, X¹¹ is C^(R11).

In some embodiments, X¹¹ is CR¹¹, wherein R¹¹ is selected from H, D,halo, oxo, CN, OH, NH₂, and C₁₋₆ alkyl.

In some embodiments, X¹¹ is CH.

In some embodiments, X¹¹ is C(R¹¹)₂, wherein each R¹¹ is independentlyselected from H, D, halo, oxo, CN, OH, NH₂, and C₁₋₆ alkyl.

In some embodiments, X¹¹ is CH₂.

In some embodiments:

X⁷ is N or C;

X⁸ is N or C;

X⁹ is N or C(R⁹)₂;

X¹⁰ is N or NR^(10N); and

X¹¹ is N, CR¹¹ or C(R¹¹)₂.

In some embodiments:

X⁷ is C;

X⁸ is C;

X⁹ is N or C(R⁹)₂;

X¹⁰ is N or NR^(10N); and

X¹¹ is N, CR¹¹ or C(RU)₂.

In some embodiments:

each bond symbol represented by

is independently a single or double bond;

R¹ is selected from H, D, C₁₋₆ alkyl, C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)NR^(c1)(OR^(a1)), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

each R^(a1), R^(b1), R^(d1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆-C₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆-C₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆-C₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a1), R^(b1), R^(c1)and R^(d1) are each optionally substituted with 1, 2, 3, or 4independently selected R^(1A) substituents;

each R^(1A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂;

X² is N;

R³ is selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

X⁴ is N or CR⁴;

X⁵ is N or CR⁵;

R⁴ and R⁵ are each independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

X⁶ is N or CR⁶;

R⁶ is selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), andS(O)₂NR^(c6)R^(d6);

each R^(b6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

X⁷ is N or C;

X⁸ is N or C;

X⁹ is N or C(R⁹)₂;

X¹⁰ is N or NR^(10N);

X¹¹ is N, CR¹¹, or C(R¹¹)₂;

each R⁹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl, of R⁹ are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents;

or, alternatively, two R⁹ groups together form an oxo group;

R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆-C₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are eachoptionally substituted with 1, 2, 3, or 4 independently selectedR^(10NA) substituents;

each R^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂;

each R¹¹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl with 1 or 2 independently selected R^(11A)substituents; and each R^(11A) is selected from H, D, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂.

In some embodiments:

each bond symbol represented by

is independently a single or double bond;

R¹ is selected from H, D, C₁₋₆ alkyl, C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)NR^(c1)(OR^(a1)), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), S(O)₂NR^(c1)R^(d1), 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein the 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are optionallysubstituted with 1 or 2 independently selected R^(1A) substituents;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a1), R^(b1), Rcl andR^(d1) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(1A) substituents;

each R^(1A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, NH₂ and C(O)R^(b11);

each R^(b11) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,and C₃₋₁₀ cycloalkyl, wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₁₀cycloalkyl of R^(b11) are each optionally substituted with 1 or 2independently selected R^(M) substituents;

each R^(M) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

X² is N;

R³ is selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

X⁴ is N or CR⁴;

X⁵ is N or CR⁵;

R⁴ and R⁵ are each independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

X⁶ is N or CR⁶;

R⁶ is selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), andS(O)₂NR^(c6)R^(d6);

each R^(b6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

X⁷ is N or C;

X⁸ is N or C;

X⁹ is N or C(R⁹)₂;

X¹⁰ is N or NR^(10N);

X¹¹ is N, CR¹¹, or C(R¹¹)₂;

each R⁹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl, of R⁹ are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents;

or, alternatively, two R⁹ groups together form an oxo group;

R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆-C₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆-C₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are eachoptionally substituted with 1, 2, 3, or 4 independently selectedR^(10NA) substituents;

each R^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂;

each R¹¹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl with 1 or 2 independently selected R^(11A)substituents; and

each R^(11A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂.

In some embodiments:

each bond symbol represented by

is independently a single or double bond;

R¹ is selected from H, C(O)R^(b1), C(O)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), and NR^(c1)C(O)NR^(c1)R^(d1);

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkylof R^(a1), R^(b1), R and R^(d1) are each optionally substituted with 1or 2 independently selected R^(1A) substituents;

each R^(1A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂;

X² is N;

R³ is H;

X⁴ is CR⁴;

X⁵ is CR⁵;

R⁴ and R⁵ are each independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

X⁶ is CR⁶;

R⁶ is selected from H, C₁₋₆ alkyl, S(O)R^(b6), and S(O)₂R^(b6);

R^(b6) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

X⁷ is C;

X⁸ is C;

X⁹ is N or C(R⁹)₂;

X¹⁰ is N or NR^(10N);

X¹¹ is N, CR¹¹, or C(R¹¹)₂;

each R⁹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl, of R⁹ are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents;

or, alternatively, two R⁹ groups together form an oxo group;

R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆-C₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are eachoptionally substituted with 1, 2, 3, or 4 independently selectedR^(10NA) substituents;

each R^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂;

each R¹¹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

each bond symbol represented by

is independently a single or double bond;

R¹ is selected from H, C(O)R^(b1), C(O)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryland 4-7 membered heterocycloalkyl are optionally substituted with 1 or 2independently selected R^(1A) substituents;

each R^(a1), R^(b1), R^(c), and R^(d1) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkylof R^(a1), R^(b1), R^(c1) and R^(d1) are each optionally substitutedwith 1 or 2 independently selected R^(1A) substituents;

each R^(1A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, NH₂, and C(O)R^(b1);

each R^(b11) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,and C₃₋₁₀ cycloalkyl, wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₁₀cycloalkyl of R^(b11) are each optionally substituted with 1 or 2independently selected R^(M) substituents;

each R^(M) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

X² is N;

R³ is H;

X⁴ is CR⁴;

X⁵ is CR⁵;

R⁴ and R⁵ are each independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

X⁶ is CR⁶;

R⁶ is selected from H, C₁₋₆ alkyl, S(O)R^(b6), and S(O)₂R^(b6);

R^(b6) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

X⁷ is C;

X⁸ is C;

X⁹ is N or C(R⁹)₂;

X¹⁰ is N or NR^(10N);

X¹¹ is N, CR¹¹, or C(R¹¹)₂;

each R⁹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl, of R⁹ are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents;

or, alternatively, two R⁹ groups together form an oxo group;

R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(10NA)substituents;

each R^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂;

each R¹¹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

each bond symbol represented by

is independently a single or double bond;

R¹ is selected from H, C(O)R^(b1), C(O)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), and NR^(c1)C(O)NR^(c1)R^(d1);

each R^(a1) and R^(b1) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, and 4-6 membered heterocycloalkyl, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-6 membered heterocycloalkyl of R^(a1) and R^(b1) areeach optionally substituted with 1 or 2 independently selected R^(1A)substituents;

each R^(c1), and R^(d1) is independently selected from C₂₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-6 membered heterocycloalkyl, wherein the C₂₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-6 membered heterocycloalkyl of R^(a1), R^(b1), R^(c1) and R^(d1)are each optionally substituted with 1 or 2 independently selectedR^(1A) substituents;

each R^(1A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂;

X² is N;

R³ is H;

X⁴ is CR⁴;

X⁵ is CR⁵;

R⁴ and R⁵ are each independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

X⁶ is CR⁶;

R⁶ is selected from H, C₁₋₆ alkyl, S(O)R^(b6), and S(O)₂R^(b6);

R^(b6) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

X⁷ is C;

X⁸ is C;

X⁹ is N or C(R⁹)₂;

X¹⁰ is N or NR^(10N);

X¹¹ is N, CR^(u), or C(R¹¹)₂;

each R⁹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl, of R⁹ are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents;

or, alternatively, two R⁹ groups together form an oxo group;

R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆-C₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(10NA)substituents;

each R^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂;

each R¹¹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

each bond symbol represented by

is independently a single or double bond;

R¹ is selected from H, C(O)R^(b1), C(O)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryland 4-7 membered heterocycloalkyl are optionally substituted with 1 or 2independently selected R^(1A) substituents;

each R^(a1) and R^(b1) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, and 4-6 membered heterocycloalkyl, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-6 membered heterocycloalkyl of R^(a1) and R^(b1) areeach optionally substituted with 1 or 2 independently selected R^(1A)substituents;

each R^(c1), and R^(d1) is independently selected from C₂₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-6 membered heterocycloalkyl, wherein the C₂₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-6 membered heterocycloalkyl of R^(a1), R^(b1), R^(c1) and R^(d1)are each optionally substituted with 1 or 2 independently selectedR^(1A) substituents;

each R^(1A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, NH₂, and C(O)R^(b11);

each R^(b11) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,and C₃₋₁₀ cycloalkyl, wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₁₀cycloalkyl of R^(b11) are each optionally substituted with 1 or 2independently selected R^(M) substituents;

each R^(M) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

X² is N;

R³ is H;

X⁴ is CH;

X⁵ is CH;

X⁶ is CR⁶;

R⁶ is selected from H, C₁₋₆ alkyl, S(O)R^(b6), and S(O)₂R^(b6);

R^(b6) is selected from H, and C₁₋₆ alkyl;

X⁷ is C;

X⁸ is C;

X⁹ is N or C(R⁹)₂;

X¹⁰ is NR^(10N);

X¹¹ is N, CR¹¹, or C(R¹¹)₂;

each R⁹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl, of R⁹ are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents;

or, alternatively, two R⁹ groups together form an oxo group;

R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(10NA)substituents;

each R^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂;

each R¹¹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

each bond symbol represented b

is independently a single or double bond;

R¹ is selected from H, C(O)NR^(c1)R^(d1), 5-6 membered heteroaryl, and4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl and4-7 membered heterocycloalkyl are optionally substituted with 1 or 2independently selected R^(1A) substituents;

each R^(c1) and R^(d1) is independently selected from H, C₂₋₆ alkyl and4-7 membered heterocycloalkyl;

each R^(1A) is independently selected from C₁₋₆ alkyl and C(O)R^(b1),wherein each R^(b11) is C₃₋₁₀ cycloalkyl, optionally substituted withC₁₋₆ haloalkyl;

X² is N; R³ is H; X⁴ is CH; X⁵ is CH;

X⁶ is CH or CS(O)₂Me;

X⁷ is C; X⁸ is C;

X⁹ is N or C(O);

X¹⁰ is NR^(10N);

R^(10N) is cyclopropylethyl; and

X¹¹ is N, CH, or CH₂.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ib):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (Ib), X² is N.

In some embodiments of Formula (Ib), X² is N and X⁴, X⁵, and X⁶ are eachCH.

In some embodiments, the compound of Formula (I) is a compound ofFormula (II):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (II), X² is N.

In some embodiments of Formula (II), X² is N and X⁴, X⁵, and X⁶ are eachCH.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIb):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIb), X² is N.

In some embodiments of Formula (IIb), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IIb), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIb), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIb), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIb), X² is CR².

In some embodiments of Formula (IIb), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIb), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIb), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIb), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIc):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIc), X² is N.

In some embodiments of Formula (IIc), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IIc), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIc), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIc), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIc), X² is CR².

In some embodiments of Formula (IIc), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIc), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIc), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIc), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IId):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IId), X² is N.

In some embodiments of Formula (IId), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IId), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IId), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IId), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IId), X² is CR².

In some embodiments of Formula (IId), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IId), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IId), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IId), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIe):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIe), X² is N.

In some embodiments of Formula (IIe), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IIe), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIe), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIe), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIe), X² is CR².

In some embodiments of Formula (IIe), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIe), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIe), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIe), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIf):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIf), X² is N.

In some embodiments of Formula (IIf), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IIf), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIf), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIf), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIf), X² is CR².

In some embodiments of Formula (IIf), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIf), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIf), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIf), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIg):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIg), X² is N.

In some embodiments of Formula (IIg), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IIg), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIg), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIg), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIg), X² is CR².

In some embodiments of Formula (IIg), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIg), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIg), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIg), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIh):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIh), X² is N.

In some embodiments of Formula (IIh), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IIh), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIh), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIh), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIh), X² is CR².

In some embodiments of Formula (IIh), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIh), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIh), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIh), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIi):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIi), X² is N.

In some embodiments of Formula (IIi), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IIi), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIi), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIi), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIi), X² is CR².

In some embodiments of Formula (IIi), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIi), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIi), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIi), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIj):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIj), X² is N.

In some embodiments of Formula (IIj), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IIj), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIj), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIj), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIj), X² is CR².

In some embodiments of Formula (IIj), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIj), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIj), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIj), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIk):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIk), X² is N.

In some embodiments of Formula (IIk), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IIk), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIk), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIk), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIk), X² is CR².

In some embodiments of Formula (IIk), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIk), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIk), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIk), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIm):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIm), X² is N.

In some embodiments of Formula (IIm), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IIm), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIm), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIm), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIm), X² is CR².

In some embodiments of Formula (IIm), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIm), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIm), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIm), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIn):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIn), X² is N.

In some embodiments of Formula (IIn), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IIn), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIn), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIn), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIn), X² is CR².

In some embodiments of Formula (IIn), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIn), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIn), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIn), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIo):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIo), X² is N.

In some embodiments of Formula (IIo), X² is N, X⁴ is CR⁴, and X⁵ is CR⁵.

In some embodiments of Formula (IIo), X² is N, X⁴ is CH, and X⁵ is CH.

In some embodiments of Formula (IIo), X² is N, X⁴ is CR⁴, and X⁵ is N.

In some embodiments of Formula (IIo), X² is N, X⁴ is N, and X⁵ is CR⁵.

In some embodiments of Formula (IIo), X² is N, X⁴ is N, and X⁵ is N.

In some embodiments of Formula (IIo), X² is CR².

In some embodiments of Formula (IIo), X² is CR², X⁴ is CR⁴, and X⁵ isCR⁵.

In some embodiments of Formula (IIo), X² is CR², X⁴ is CR⁴, and X⁵ is N.

In some embodiments of Formula (IIo), X² is CR², X⁴ is N, and X⁵ is CR⁵.

In some embodiments of Formula (IIo), X² is CR², X⁴ is N, and X⁵ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIp):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIp), X² is N.

In some embodiments of Formula (IIp), X² is N, X⁴ is CR⁴, X⁵ is CR⁵, andX⁶ is CR⁶.

In some embodiments of Formula (IIp), X² is N, X⁴ is CR⁴, X⁵ is CR⁵, andX⁶ is N.

In some embodiments of Formula (IIp), X² is N, X⁴ is CR⁴, X⁵ is N, andX⁶ is CR⁶.

In some embodiments of Formula (IIp), X² is N, X⁴ is CR⁴, X⁵ is N, andX⁶ is N.

In some embodiments of Formula (IIp), X² is N, X⁴ is CH, X⁵ is CH, andX⁶ is CR⁶.

In some embodiments of Formula (IIp), X² is CR².

In some embodiments of Formula (IIp), X² is CR², X⁴ is CR⁴, X⁵ is CR⁵,and X⁶ is CR⁶.

In some embodiments of Formula (IIp), X² is CR², X⁴ is CR⁴, X⁵ is CR⁵,and X⁶ is N.

In some embodiments of Formula (IIp), X² is CR², X⁴ is CR⁴, X⁵ is N, andX⁶ is CR⁶.

In some embodiments of Formula (IIp), X² is CR², X⁴ is CR⁴, X⁵ is N, andX⁶ is N.

In some embodiments of Formula (IIp), X² is CH, X⁴ is CH, X⁵ is CH, andX⁶ is CR⁶.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIq):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIq), X² is N.

In some embodiments of Formula (IIq), X² is N, X⁴ is CR⁴, X⁵ is CR⁵, andX⁶ is CR⁶.

In some embodiments of Formula (IIq), X² is N, X⁴ is CR⁴, X⁵ is CR⁵, andX⁶ is N.

In some embodiments of Formula (IIq), X² is N, X⁴ is CR⁴, X⁵ is N, andX⁶ is CR⁶.

In some embodiments of Formula (IIq), X² is N, X⁴ is CR⁴, X⁵ is N, andX⁶ is N.

In some embodiments of Formula (IIq), X² is N, X⁴ is CH, X⁵ is CH, andX⁶ is CR⁶.

In some embodiments of Formula (IIq), X² is CR².

In some embodiments of Formula (IIq), X² is CR², X⁴ is CR⁴, X⁵ is CR⁵,and X⁶ is CR⁶.

In some embodiments of Formula (IIq), X² is CR², X⁴ is CR⁴, X⁵ is CR⁵,and X⁶ is N.

In some embodiments of Formula (IIq), X² is CR², X⁴ is CR⁴, X⁵ is N, andX⁶ is CR⁶.

In some embodiments of Formula (IIq), X² is CR², X⁴ is CR⁴, X⁵ is N, andX⁶ is N.

In some embodiments of Formula (IIq), X² is CH, X⁴ is CH, X⁵ is CH, andX⁶ is CR⁶.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIr):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIr), X² is N.

In some embodiments of Formula (IIr), X² is N, X⁴ is CR⁴, X⁵ is CR⁵, andX⁶ is CR⁶.

In some embodiments of Formula (IIr), X² is N, X⁴ is CR⁴, X⁵ is CR⁵, andX⁶ is N.

In some embodiments of Formula (IIr), X² is N, X⁴ is CR⁴, X⁵ is N, andX⁶ is CR⁶.

In some embodiments of Formula (IIr), X² is N, X⁴ is CR⁴, X⁵ is N, andX⁶ is N.

In some embodiments of Formula (IIr), X² is N, X⁴ is CH, X⁵ is CH, andX⁶ is CR⁶.

In some embodiments of Formula (IIr), X² is CR².

In some embodiments of Formula (IIr), X² is CR², X⁴ is CR⁴, X⁵ is CR⁵,and X⁶ is CR⁶.

In some embodiments of Formula (IIr), X² is CR², X⁴ is CR⁴, X⁵ is CR⁵,and X⁶ is N.

In some embodiments of Formula (IIr), X² is CR², X⁴ is CR⁴, X⁵ is N, andX⁶ is CR⁶.

In some embodiments of Formula (IIr), X² is CR², X⁴ is CR⁴, X⁵ is N, andX⁶ is N.

In some embodiments of Formula (IIr), X² is CH, X⁴ is CH, X⁵ is CH, andX⁶ is CR⁶.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIs), wherein:

X⁹ is N or C(O);

R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, andC(O)NR^(c1)R^(d1), wherein the C₁₋₆ alkyl is optionally substituted with1, 2, 3, or 4 independently selected R^(1A) substituents; and eachR^(c1) and R^(d1) is independently selected from H, C₁₋₆ alkyl and 4-7membered heterocycloalkyl;

R⁶ is selected from H, D, halo, C₁₋₆ alkyl, SR^(a6), C(O)R^(b6), andS(O)₂R^(b6), wherein the C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 independently selected R^(6A) substituents; each R^(a6) andR^(b6) is independently selected from H and C₁₋₆ alkyl; and each R^(6A)is selected from H, D, halo, CN, OH, NH₂, and C₁₋₆ alkyl;

R^(10N) is selected from H, C₁₋₆ alkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, andC₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-; and

X¹¹ is N or CH.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIs), wherein:

X⁹ is N or C(O);

R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, andC(O)NR^(c1)R^(d1), wherein the C₁₋₆ alkyl is optionally substituted with1, 2, 3, or 4 independently selected R^(1A) substituents; and eachR^(c1) and R^(d1) is independently selected from H, C₂₋₆ alkyl and 4-7membered heterocycloalkyl;

R⁶ is selected from H, D, halo, C₁₋₆ alkyl, SR^(a6), C(O)R^(b6), andS(O)₂R^(b6), wherein the C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 independently selected R^(6A) substituents; each R^(a6) andR^(b6) is independently selected from H and C₁₋₆ alkyl; and each R^(6A)is selected from H, D, halo, CN, OH, NH₂, and C₁₋₆ alkyl;

R^(10N) is selected from H, C₁₋₆ alkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, andC₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-; and

X¹¹ is N or CH.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIs), wherein:

X⁹ is C(O);

R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, andC(O)NR^(c1)R^(d1), wherein the C₁₋₆ alkyl is optionally substituted with1, 2, 3, or 4 independently selected R^(1A) substituents; and eachR^(c1) and R^(d1) is independently selected from H, C₁₋₆ alkyl and 4-7membered heterocycloalkyl;

R⁶ is selected from H, D, halo, C₁₋₆ alkyl, SR^(a6), C(O)R^(b6), andS(O)₂R^(b6), wherein the C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 independently selected R^(6A) substituents; each R^(a6) andR^(b6) is independently selected from H and C₁₋₆ alkyl; and each R^(6A)is selected from H, D, halo, CN, OH, NH₂, and C₁₋₆ alkyl;

R^(10N) is selected from H, C₁₋₆ alkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, andC₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-; and

X¹¹ is N or CH.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIt):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIt), X² is N.

In some embodiments of Formula (IIt), X² is N, X⁴ is CR⁴, and X⁵ is CR⁵.

In some embodiments of Formula (IIt), X² is N, X⁴ is CH, and X⁵ is CH.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIt), X² is N, X⁴ is CR⁴, and X⁵ is N.

In some embodiments of Formula (IIt), X² is N, X⁴ is N, and X⁵ is CR⁵.

In some embodiments of Formula (IIt), X² is N, X⁴ is N, and X⁵ is N.

In some embodiments of Formula (IIt), X² is CR².

In some embodiments of Formula (IIt), X² is CR², X⁴ is CR⁴, and X⁵ isCR⁵.

In some embodiments of Formula (IIt), X² is CR², X⁴ is CR⁴, and X⁵ is N.

In some embodiments of Formula (IIt), X² is CR², X⁴ is N, and X⁵ is CR⁵.

In some embodiments of Formula (IIt), X² is CR², X⁴ is N, and X⁵ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIu):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a1), SR^(a1),NHOR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)NR^(c1)(OR^(a1)),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), andNR^(c1)C(O)NR^(c1)R^(d1), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R¹ are each optionally substituted with1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(1A) substituents;

each R^(a1), R^(b1), and R^(c1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a1), R^(b1), and R^(c1) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(1A) substituents;

each R^(d1) is independently selected from C₂₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₂₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₂₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₂₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(d1) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(1A) substituents;

or, any R^(c1) and R^(d1), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(1A) substituents;

each R^(1A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a1),SR^(a11), NHOR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11),C(O)NR^(c111)(OR^(a11)), C(O)OR^(a11), OC(O)R^(b11),OC(O)NR^(c11)R^(d11), NR^(c11)R^(d11), NR^(c11)NR^(c11)R^(d11),NR¹¹C(O)R^(b11), NR^(c11)C(O)OR^(a11), NR^(c11)C(O)NR^(c11)R^(d11),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R^(1A) are each optionally substituted with 1, 2, 3, 4, 5, 6,7, or 8 independently selected R^(M) substituents;

each R^(a11), R^(b11), R^(c11), and R^(d11) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of Rail, R^(b11), R^(c11)and R^(d11) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or8 independently selected R^(M) substituents;

or, any R^(c11) and R^(d11), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(M) substituents;

each R^(M) is independently selected from D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃alkylcarbonyloxy, aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy, di(C₁₋₃alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino;

R⁶ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a6), SR^(a6),NHOR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)NR⁶(OR^(a6)), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR⁶NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6),C(═NR^(e6))R^(b6), C(═NOH)R^(b6), C(═NCN)R^(b6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NOH)NR^(c6)R^(d6), NR⁶C(═NCN)NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))R^(b6), NR^(c6)S(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)(═NR^(e6))R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),S(O)₂NR^(c6)R^(d6), S(O)(═NR^(e6))R^(b6), OS(O)(═NR^(e6))R^(b6),OS(O)₂R^(b6), and SF₅, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁶ are each optionally substituted with1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(6A) substituents;

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a6), R^(b6), R^(c6)and R^(d6) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or8 independently selected R^(6A) substituents;

or, any R^(c6) and R^(d6), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(6A) substituents;

each R^(e6) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(6A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆-C₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a61),SR^(a61), NHOR^(a61), C(O)R^(b61), C(O)NR^(c61)R^(d61),C(O)NR^(c61)(OR^(a61)), C(O)OR^(a61), OC(O)R^(b61),OC(O)NR^(c61)R^(d61), NR^(c61)R^(d61), NR^(c61)NR^(c61)R^(d61),NR^(c61)C(O)R^(b61), NR^(c61)C(O)OR^(a61), NR^(c61)C(O)NR^(c61)R^(d61),C(═NR^(e61))R^(b61), C(═NOH)R^(b61), C(═NCN)R^(b61),C(═NR^(e6))NR^(c61)R^(d61), NR^(c61)C(═NR^(e61))NR^(c61)R^(d61),NR^(c61)C(═NOH)NR^(c61)R^(d61), NR^(c61)C(═NCN)NR^(c61)R^(d61),NR^(c61)C(═NR^(e61))R^(b61), NR^(c61)S(O)NR^(c61)R^(d61),NR^(c61)S(O)R^(b61), NR^(c61)S(O)₂R^(b61),NR^(c61)S(O)(═NR^(e61))R^(b61), NR^(c61)S(O)₂NR^(c61)R^(d61),S(O)R^(b61), S(O)NR^(c61)R^(d61), S(O)₂R^(b61), S(O)₂NR^(c61)R^(d61),S(O)(═NR^(e61))R^(b61), OS(O)(═NR^(e61))R^(b61), OS(O)₂R^(b61), and SF₅,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R^(6A) are each optionally substituted with 1, 2, 3, 4, 5, 6,7, or 8 independently selected R^(M) substituents;

each R^(a61), R^(b61), R^(c61), and R^(d61) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a6), R^(b61), R^(c61)and R^(d61) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or8 independently selected R^(M) substituents;

or, any R^(c61) and R^(d61), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(M) substituents;

each R^(e61) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

X⁹ is NR⁹N or C(R⁹)₂;

X¹¹ is NR^(11N) or C(R¹¹)₂;

R^(9N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b9N), C(O)NR^(9N)R^(d9N),C(O)OR^(a9N), C(═NR^(e9N))R^(b9N)C(═NR^(e9)N)NR^(c9)NR^(d9)N,C(═NCN)NR⁹NR^(d9)N, C(═NOR^(a9)N)NR^(c9N), S(O)₂R^(b9N),S(O)(═NR^(c9N))R^(d9)N and S(O)₂NR^(9N)R^(d9N), wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(9N) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(9NA) substituents;

each R^(a9N), R^(b9N), R^(c9N), and R^(d9N) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a9)N, R^(b9N),R^(c9N), and R^(d9N) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(9NA) substituents;

or, any R^(c9N) and R^(d9N), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(9NA) substituents;

each R^(e9N) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(9NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a9N2), SR^(a9N2),NHOR^(a9N2), C(O)R^(b9N2), C(O)NR^(9N2)R^(d9N2),C(O)NR^(c9N2)(OR^(a9N2)), C(O)OR^(a9N2), OC(O)R^(b9N2),OC(O)NR^(c9N2)R^(d9N2), NR^(c9N2)R^(d9N2), NR^(c9N2)NR^(c9N2)R^(d9N2),NR^(c9N2)C(O)R^(b9N2), NR^(c9N2)C(O)OR^(a9N2), andNR^(9N2)C(O)NR^(9N2)R^(d9N2), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(9NA) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a9N2), R^(b9N2), R^(c9N2), and R^(d9N2) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a9N2), R^(b9N2), R^(c9N2) andR^(d9N2) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents;

or, any R^(c9N2) and R^(d9N2), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-6 memberedheteroaryl group or a 4-7 membered heterocycloalkyl group, wherein the5-6 membered heteroaryl group or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R⁹ is independently selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a91), SR^(a91), NHOR^(a91), C(O)R^(b91),C(O)NR^(c91)R^(d91), C(O)NR^(c91)(OR^(a91)), C(O)OR^(a91), OC(O)R^(b91),OC(O)NR^(c91)R^(d91), NR^(c91)R^(d91), NR^(c91)NR^(c91)R^(d91),NR^(c91)C(O)R^(b91), NR^(c91)C(O)OR^(a91), andNR^(c91)C(O)NR^(c91)R^(d91), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁹ are each optionally substituted with1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(9A) substituents;

or, alternatively, two R⁹ groups together form an oxo group;

each R^(a91), R^(b91), R^(c91), and R^(d91) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a91), R^(b91),R^(c91) and R^(d91) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(9A) substituents;

or, any R^(c91) and R^(d91), attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylgroup or a 4-10 membered heterocycloalkyl group, wherein the 5-10membered heteroaryl group or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(9A) substituents;

each R^(9A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a92), SR^(a92),NHOR^(a92), C(O)R^(b92), C(O)NR^(c92)R^(d92), C(O)NR^(c92)(OR^(a92)),C(O)OR^(a92), OC(O)R^(b92), OC(O)NR^(c92)R^(d92), NR^(c92)R^(d92),NR^(c92)NR^(c92)R^(d92), NR^(c92)C(O)R^(b92), NR^(c92)C(O)OR^(a92), andNR^(c92)C(O)NR^(c92)R^(d92), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(9A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a92), R^(b92), R^(c92), and R^(d92) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a92), R^(b92), R^(c92) and R^(d92) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

or, any R^(c92) and R^(d92), attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroarylgroup or a 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl group or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b10N), C(O)NR^(c10N)R^(d10N),C(O)OR^(a10N), C(═NR^(e10N))R^(b10N), C(═NR^(e10N))NR^(c10N)R^(d10N),C(═NCN)NR^(c10N)R^(d10N), C(═NOR^(a10N))NR^(c10N), S(O)₂R^(b10N),S(O)(═NR^(c10N))R^(d10N), and S(O)₂NR^(e10N)R^(d10N), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(10NA) substituents;

each R^(a10N), R^(b10N), R^(c10N), and R^(d10N) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a10N), R^(b10N),R^(c10N), and R^(d10N) are each optionally substituted with 1, 2, 3, 4,5, 6, 7, or 8 independently selected R^(10NA) substituents;

or, any R^(c10N) and R^(d10N), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-10 memberedheteroaryl group or a 4-10 membered heterocycloalkyl group, wherein the5-10 membered heteroaryl group or 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(10NA) substituents;

each R^(e10N) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a10N2), SR^(a10N2),NHOR^(a10N2), C(O)R^(b10N2), C(O)NR^(c10N2)R^(d10N2),C(O)NR^(c10N2)(OR^(a10N2)), C(O)OR^(a10N2), OC(O)R^(b10N2),OC(O)NR^(c10N2)R^(d10N2), NR^(c10N2)R^(d10N2),NR^(c10N2)NR^(c10N2)R^(d10N2), NR^(c10N2)C(O)R^(b10N2),NR^(c10N2)C(O)OR^(a10N2), and NR^(c10N2)C(O)NR^(c10N2)R^(d10N2), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10NA) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(a10N2), R^(b10N2), R^(c10N2), and R^(d10N2) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a10N2), R^(b10N2), R^(c10N2) andR^(d10N2) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents;

or, any R^(c10N2) and R^(d10N2), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-6 memberedheteroaryl group or a 4-7 membered heterocycloalkyl group, wherein the5-6 membered heteroaryl group or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

R^(11N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b11)N, C(O)NR^(c1)NR^(d11)N,C(O)OR^(a11N), C(═NR^(e11N))R^(b11N), C(═NR^(e11N))NR^(c11)NR^(d11N),C(═NCN)NR^(c11)NR^(d11)N, C(═NOR^(a11N))NR^(c11N)S(O)₂R^(b11)NS(O)(═NR^(c11N))R^(d11)N, and S(O)₂NR^(c11N)R^(d11)N, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(11N) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(11NA) substituents;

each R^(a11N), R^(b111N), R^(c11N), and R^(d11N) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a11N), R^(b111N),R^(c11N), and R^(d11N) are each optionally substituted with 1, 2, 3, 4,5, 6, 7, or 8 independently selected R^(11NA) substituents;

or, any R^(c11N) and R^(d11N), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-10 memberedheteroaryl group or a 4-10 membered heterocycloalkyl group, wherein the5-10 membered heteroaryl group or 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(11NA) substituents;

each R^(e11N) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(11NA) is independently selected from H, D, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a11N2), SR^(a11N2),NHOR^(a11N2), C(O)R^(b11N2), C(O)NR^(c11N2)R^(d11N2),C(O)NR^(c11N2)(OR^(a11N2)), C(O)OR^(a11N2), OC(O)R^(b11N2)OC(O)NR^(c11N2)R^(d11N2), NR^(c11N2)R^(d11N2),NR^(c11N2)NR^(c11N2)R^(d11N2), NR^(c11N2)C(O)R^(b11N2),NR^(c11N2)C(O)OR^(a11N2), and NR^(c11N2)C(O)NR^(c11N2)R^(d11N2), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(11NA) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(a11N2), R^(b11N2), R^(c11N2), and R^(d11N2) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a11N2), R^(b11N2), R^(c11N2) andR^(d11N2) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents;

or, any R^(c11N2) and R^(d11N2), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-6 memberedheteroaryl group or a 4-7 membered heterocycloalkyl group, wherein the5-6 membered heteroaryl group or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R¹¹ is independently selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a111), SR^(a111), NHOR^(a111), C(O)R^(b111),C(O)NR^(c11)R^(d111), C(O)NR^(c111)(OR^(a111)), C(O)OR^(a111),OC(O)R^(b111), OC(O)NR^(c111)R^(d111), NR^(c111)R^(d111),NR^(c111)NR^(c111)R^(d111), NR^(c111)C(O)R^(b111),NR^(c111)C(O)OR^(a111), and NR^(c111)C(O)NR^(c111)R^(d111), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R¹ are each optionally substituted with 1, 2, 3, 4, 5, 6, 7,or 8 independently selected R^(11A) substituents;

each R^(a111), R^(b111), R^(c111), and R^(d111) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a111), R^(b111),R^(c111) and R^(d111) are each optionally substituted with 1, 2, 3, 4,5, 6, 7, or 8 independently selected R^(11A) substituents;

or, any R^(c111) and R^(d111), attached to the same N atom, togetherwith the N atom to which they are attached, form a 5-10 memberedheteroaryl group or a 4-10 membered heterocycloalkyl group, wherein the5-10 membered heteroaryl group or 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(11A) substituents; and

each R^(11A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a112), SR^(a112),NHOR^(a112), C(O)R^(b112), C(O)NR^(c112)R^(d112),C(O)NR^(c112)(OR^(a112)), C(O)OR^(a112), OC(O)R^(b112),OC(O)NR^(c112)R^(d112), NR^(c112)R^(d112), NR^(c112)NR^(c112)R^(d112),NR^(c112)C(O)R^(b112), NR^(c112)C(O)OR^(a112), andNR^(c112)C(O)NR^(c112)R^(d112), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(11A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; and

each R^(a112), R^(b112), R^(c112), and R^(d112) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a112), R^(b112), R^(c112) andR^(d112) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents; or, any R^(c112) andR^(a112), attached to the same N atom, together with the N atom to whichthey are attached, form a 5-6 membered heteroaryl group or a 4-7membered heterocycloalkyl group, wherein the 5-6 membered heteroarylgroup or 4-7 membered heterocycloalkyl group is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents.

In some embodiments of Formula (IIu), X⁹ is C(R⁹)₂ and X¹¹ is C(R¹¹)₂.

In some embodiments of Formula (IIu), X⁹ is NR^(9N) and X¹¹ is C(R¹¹)₂.

In some embodiments of Formula (IIu), X⁹ is C(R⁹)₂ and X¹¹ is NR^(11N).

In some embodiments of Formula (IIu), X⁹ is C(O) and X¹¹ is C(R¹¹)₂.

In some embodiments of Formula (IIu), X⁹ is C(O) and X¹¹ is CH₂.

In some embodiments of Formula (IIu), X⁹ is C(R⁹)₂ and X¹¹ is C(O).

In some embodiments of Formula (IIu), X⁹ is CH₂ and X¹¹ is C(O).

In some embodiments of Formula (IIu):

R¹ is selected from H, D, C₁₋₆ alkyl, C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)NR^(c1)(OR^(a1)), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), and NR^(c1)C(O)NR^(c1)R^(d1);

each R^(a1), R^(b1), and R^(c1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a1), R^(b1), and R^(c1) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(1A)substituents;

each R^(d1) is independently selected from C₂₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀₀ aryl-C₂₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₂₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₂₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(d1) isoptionally substituted with 1, 2, 3, or 4 independently selected R^(1A)substituents;

each R^(1A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂;

R⁶ is selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), andS(O)₂NR^(c6)R^(d6);

each R^(b6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆-C₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

X⁹ is C(R⁹)₂;

X¹¹ is C(R¹¹)₂;

each R⁹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl, of R⁹ are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents;

or, alternatively, two R⁹ groups together form an oxo group;

R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(10NA)substituents;

each R^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂;

each R¹¹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl with 1 or 2 independently selected R^(11A)substituents; and

each R^(11A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂.

In some embodiments of Formula (IIu):

R¹ is selected from H, D, C₁₋₆ alkyl, C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)NR^(c1)(OR^(a1)), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), S(O)₂NR^(c1)R^(d1), 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein the 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are optionallysubstituted with 1 or 2 independently selected R^(1A) substituents;

each R^(a1), R^(b1), and R^(c1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a1), R^(b1), and R^(c1) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(1A)substituents;

each R^(d1) is independently selected from C₂₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₂₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₂₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₂₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(d1) isoptionally substituted with 1, 2, 3, or 4 independently selected R^(1A)substituents;

each R^(1A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, NH₂, and C(O)R^(b11);

each R^(b11) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,and C₃₋₁₀ cycloalkyl, wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₁₀cycloalkyl of R^(b11) are each optionally substituted with 1 or 2independently selected R^(M) substituents;

each R^(M) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;R⁶ is selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), andS(O)₂NR^(c6)R^(d6);

each R^(b6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

X⁹ is C(R⁹)₂;

X¹¹ is C(R¹¹)₂;

each R⁹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl, of R⁹ are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents;

or, alternatively, two R⁹ groups together form an oxo group;

R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(10NA)substituents;

each R^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂;

each R¹¹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl with 1 or 2 independently selected R^(11A)substituents; and

each R^(11A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂.

In some embodiments of Formula (IIu):

R¹ is selected from H, C(O)R^(b1), C(O)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), and NR^(c1)C(O)NR^(c1)R^(d1);

each R^(a1), R^(b1), and R^(c1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkylof R^(a1), R^(b1) and R^(c1) are each optionally substituted with 1 or 2independently selected R^(1A) substituents;

each R^(d1) is independently selected from H, C₂₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, and 4-6 membered heterocycloalkyl, wherein the C₂₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-6 membered heterocycloalkyl of R^(d1) is optionallysubstituted with 1 or 2 independently selected R^(1A) substituents;

each R^(1A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂;

R⁶ is selected from H, C₁₋₆ alkyl, S(O)R^(b6), and S(O)₂R^(b6);

R^(b6) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

X⁹ is C(R⁹)₂;

X¹¹ is C(R¹¹)₂;

each R⁹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl, of R⁹ are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents;

or, alternatively, two R⁹ groups together form an oxo group;

R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(10NA)substituents;

each R^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂; and

each R¹¹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formula (IIu):

R¹ is selected from H, C(O)R^(b1), C(O)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryland 4-7 membered heterocycloalkyl are optionally substituted with 1 or 2independently selected R^(1A) substituents;

each R^(a1), R^(b1), and R^(c1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkylof R^(a1), R^(b1) and R^(c1) are each optionally substituted with 1 or 2independently selected R^(1A) substituents;

each R^(d1) is independently selected from H, C₂₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, and 4-6 membered heterocycloalkyl, wherein the C₂₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-6 membered heterocycloalkyl of R^(d1) is optionallysubstituted with 1 or 2 independently selected R^(1A) substituents;

each R^(1A) is independently selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, NH₂, and C(O)R^(b1);

each R^(b11) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,and C₃₋₁₀ cycloalkyl, wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₁₀cycloalkyl of R^(b11) are each optionally substituted with 1 or 2independently selected R^(M) substituents;

each R^(M) is independently selected from C₁₋₃ alkyl and C₁₋₃ haloalkyl;

R⁶ is selected from H, C₁₋₆ alkyl, S(O)R^(b6), and S(O)₂R^(b6);

R^(b6) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

X⁹ is C(R⁹)₂;

X¹¹ is C(R¹¹)₂;

each R⁹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl, of R⁹ are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents;

or, alternatively, two R⁹ groups together form an oxo group;

R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(10NA)substituents;

each R^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂; and

each R¹¹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formula (IIu):

R¹ is selected from H, C(O)NR^(c1)R^(d1), 5-6 membered heteroaryl, and4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl and4-7 membered heterocycloalkyl are optionally substituted with 1 or 2independently selected R^(1A) substituents;

each R^(c1) and R^(d1) is independently selected from H, C₂₋₆ alkyl and4-7 membered heterocycloalkyl;

each R^(1A) is independently selected from C₁₋₆ alkyl and C(O)R^(b11),wherein each R^(b11) is C₃₋₁₀ cycloalkyl, optionally substituted withC₁₋₆ haloalkyl;

R⁶ is selected from H and S(O)₂Me;

X⁹ is C(O);

X¹¹ is CH₂; and

R^(10N) is cyclopropylethyl.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIv):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIv) X⁹ is C(R⁹)₂ and X¹¹ is C(R¹¹)₂.

In some embodiments of Formula (IIv), X⁹ is NR^(9N) and X¹¹ is CR¹¹.

In some embodiments of Formula (IIv), X⁹ is C(R⁹)₂ and X¹¹ is NR^(11N).

In some embodiments of Formula (IIv), X⁹ is C(O) and X¹¹ is C(R¹¹)₂.

In some embodiments of Formula (IIv), X⁹ is C(O) and X¹¹ is CH₂.

In some embodiments of Formula (IIv), X⁹ is C(R⁹)₂ and X¹¹ is C(O).

In some embodiments of Formula (IIv), X⁹ is CH₂ and X¹¹ is C(O).

In some embodiments of Formula (IIv), X⁹ is N and X¹¹ is N.

In some embodiments of Formula (IIv), X⁹ is N and X¹¹ is CH.

In some embodiments of Formula (IIv):

R¹ is H;

R⁶ is selected from H and Me;

X⁹ is N;

X¹¹ is CH or N; and

R^(10N) is cyclopropylethyl.

In some embodiments, the compound of Formula (I) is a compound ofFormula (III):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (III), X² is N.

In some embodiments of Formula (III), X² is N and X⁴, X⁵ and X⁶ are eachCH.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIIb):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIIb), X² is N.

In some embodiments of Formula (IIIb), X² is N, X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIIb), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIIb), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIIb), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIIb), X² is CR².

In some embodiments of Formula (IIIb), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIIb), X² is CR², X⁵ is CR⁵, and X⁶ isN.

In some embodiments of Formula (IIIb), X² is CR², X⁵ is N, and X⁶ isCR⁶.

In some embodiments of Formula (IIIb), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIIc):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIIc), X² is N.

In some embodiments of Formula (IIIc), X² is N, X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIIc), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIIc), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIIc), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIIc), X² is CR².

In some embodiments of Formula (IIIc), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIIc), X² is CR², X⁵ is CR⁵, and X⁶ isN.

In some embodiments of Formula (IIIc), X² is CR², X⁵ is N, and X⁶ isCR⁶.

In some embodiments of Formula (IIIc), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIId):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIId), X² is N.

In some embodiments of Formula (IIId), X² is N, X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIId), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIId), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIId), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIId), X² is CR².

In some embodiments of Formula (IIId), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIId), X² is CR², X⁵ is CR⁵, and X⁶ isN.

In some embodiments of Formula (IIId), X² is CR², X⁵ is N, and X⁶ isCR⁶.

In some embodiments of Formula (IIId), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIIe):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIIe), X² is N.

In some embodiments of Formula (IIIe), X² is N, X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIIe), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIIe), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIIe), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIIe), X² is CR².

In some embodiments of Formula (IIIe), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIIe), X² is CR², X⁵ is CR⁵, and X⁶ isN.

In some embodiments of Formula (IIIe), X² is CR², X⁵ is N, and X⁶ isCR⁶.

In some embodiments of Formula (IIIe), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIIf):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIIf), X² is N.

In some embodiments of Formula (IIIf), X² is N, X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIIf), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIIf), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIIf), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIIf), X² is CR².

In some embodiments of Formula (IIIf), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIIf), X² is CR², X⁵ is CR⁵, and X⁶ isN.

In some embodiments of Formula (IIIf), X² is CR², X⁵ is N, and X⁶ isCR⁶.

In some embodiments of Formula (IIIf), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIIg):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIIg), X² is N.

In some embodiments of Formula (IIIg), X² is N, X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIIg), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIIg), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIIg), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIIg), X² is CR².

In some embodiments of Formula (IIIg), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIIg), X² is CR², X⁵ is CR⁵, and X⁶ isN.

In some embodiments of Formula (IIIg), X² is CR², X⁵ is N, and X⁶ isCR⁶.

In some embodiments of Formula (IIIg), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIIh):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIIh), X² is N.

In some embodiments of Formula (IIIh), X² is N, X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIIh), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IIIh), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IIIh), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IIIh), X² is CR².

In some embodiments of Formula (IIIh), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IIIh), X² is CR², X⁵ is CR⁵, and X⁶ isN.

In some embodiments of Formula (IIIh), X² is CR², X⁵ is N, and X⁶ isCR⁶.

In some embodiments of Formula (IIIh), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIIi):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIIi), X² is N.

In some embodiments of Formula (IIi), X² is N, X⁴ is CR⁴, X⁵ is CR⁵, andX⁶ is CR⁶.

In some embodiments of Formula (IIIi), X² is N, X⁴ is CR⁴, X⁵ is CR⁵,and X⁶ is N.

In some embodiments of Formula (IIIi), X² is N, X⁴ is CR⁴, X⁵ is N, andX⁶ is CR⁶.

In some embodiments of Formula (IIIi), X² is N, X⁴ is CR⁴, X⁵ is N, andX⁶ is N.

In some embodiments of Formula (IIIi), X² is N, X⁴ is CH, X⁵ is CH, andX⁶ is CR⁶.

In some embodiments of Formula (IIIi), X² is CR².

In some embodiments of Formula (IIIi), X² is CR², X⁴ is CR⁴, X⁵ is CR⁵,and X⁶ is CR⁶.

In some embodiments of Formula (IIIi), X² is CR², X⁴ is CR⁴, X⁵ is CR⁵,and X⁶ is N.

In some embodiments of Formula (IIIi), X² is CR², X⁴ is CR⁴, X⁵ is N,and X⁶ is CR⁶.

In some embodiments of Formula (IIIi), X² is CR², X⁴ is CR⁴, X⁵ is N,and X⁶ is N.

In some embodiments of Formula (IIIi), X² is CH, X⁴ is CH, X⁵ is CH, andX⁶ is CR⁶.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IIIj):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIIj), X² is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IV):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IV), X² is N.

In some embodiments of Formula (IV), X² is N and X⁴, X⁵ and X⁶ are eachCH.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IVb):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IVb), X² is N.

In some embodiments of Formula (IVb), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IVb), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVb), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVb), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IVb), X² is CR².

In some embodiments of Formula (IVb), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IVb), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVb), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVb), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IVc):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IVc), X² is N.

In some embodiments of Formula (IVc), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IVc), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVc), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVc), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IVc), X² is CR².

In some embodiments of Formula (IVc), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IVc), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVc), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVc), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IVd):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IVd), X² is N.

In some embodiments of Formula (IVd), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IVd), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVd), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVd), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IVd), X² is CR².

In some embodiments of Formula (IVd), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IVd), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVd), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVd), wherein X² is CR², X⁵ is N, and X⁶is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IVe):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IVe), X² is N.

In some embodiments of Formula (IVe), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IVe), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVe), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVe), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IVe), X² is CR².

In some embodiments of Formula (IVe), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IVe), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVe), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVe), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IVf):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IVf), X² is N.

In some embodiments of Formula (IVf), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IVf), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVf), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVf), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IVf), X² is CR².

In some embodiments of Formula (IVf), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IVf), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVf), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVf), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IVg):

or a pharmaceutically acceptable salt thereof.

In some embodiment sound of Formula (IVg), X² is N.

In some embodiments of Formula (IVg), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IVg), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVg), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVg), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IVg), X² is CR².

In some embodiments of Formula (IVg), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IVg), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVg), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVg), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IVh):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IVh), X² is N.

In some embodiments of Formula (IVh), X² is N, X⁵ is CR⁵, and X⁶ is CR⁶.

In some embodiments of Formula (IVh), X² is N, X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVh), X² is N, X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVh), X² is N, X⁵ is N, and X⁶ is N.

In some embodiments of Formula (IVh), X² is CR².

In some embodiments of Formula (IVh), X² is CR², X⁵ is CR⁵, and X⁶ isCR⁶.

In some embodiments of Formula (IVh), X² is CR², X⁵ is CR⁵, and X⁶ is N.

In some embodiments of Formula (IVh), X² is CR², X⁵ is N, and X⁶ is CR⁶.

In some embodiments of Formula (IVh), X² is CR², X⁵ is N, and X⁶ is N.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IVj):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IVj), X² is N.

In some embodiments of Formula (IVj), X² is N, X⁴ is CR⁴, X⁵ is CR⁵, andX⁶ is CR⁶.

In some embodiments of Formula (IVj), X² is N, X⁴ is CR⁴, X⁵ is CR⁵, andX⁶ is N.

In some embodiments of Formula (IVj), X² is N, X⁴ is CR⁴, X⁵ is N, andX⁶ is CR⁶.

In some embodiments of Formula (IVj), X² is N, X⁴ is CR⁴, X⁵ is N, andX⁶ is N.

In some embodiments of Formula (IVj), X² is N, X⁴ is CH, X⁵ is CH, andX⁶ is CR⁶.

In some embodiments of Formula (IVj), X² is CR².

In some embodiments of Formula (IVj), X² is CR², X⁴ is CR⁴, X⁵ is CR⁵,and X⁶ is CR⁶.

In some embodiments of Formula (IVj), X² is CR², X⁴ is CR⁴, X⁵ is CR⁵,and X⁶ is N.

In some embodiments of Formula (IVj), X² is CR², X⁴ is CR⁴, X⁵ is N, andX⁶ is CR⁶.

In some embodiments of Formula (IVj), X² is CR², X⁴ is CR⁴, X⁵ is N, andX⁶ is N.

In some embodiments of Formula (IVj), X² is CH, X⁴ is CH, X⁵ is CH, andX⁶ is CR⁶.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IVk):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IVk), X² is N.

In some embodiments of Formula (IVk), X² is N, X⁴ is CR⁴, X⁵ is CR⁵, andX⁶ is CR⁶.

In some embodiments of Formula (IVk), X² is N, X⁴ is CR⁴, X⁵ is CR⁵, andX⁶ is N.

In some embodiments of Formula (IVk), X² is N, X⁴ is CR⁴, X⁵ is N, andX⁶ is CR⁶.

In some embodiments of Formula (IVk), X² is N, X⁴ is CR⁴, X⁵ is N, andX⁶ is N.

In some embodiments of Formula (IVk), X² is N, X⁴ is CH, X⁵ is CH, andX⁶ is CR⁶.

In some embodiments of Formula (IVk), X² is CR².

In some embodiments of Formula (IVk), X² is CR², X⁴ is CR⁴, X⁵ is CR⁵,and X⁶ is CR⁶.

In some embodiments of Formula (IVk), X² is CR², X⁴ is CR⁴, X⁵ is CR⁵,and X⁶ is N.

In some embodiments of Formula (IVk), X² is CR², X⁴ is CR⁴, X⁵ is N, andX⁶ is CR⁶.

In some embodiments of Formula (IVk), X² is CR², X⁴ is CR⁴, X⁵ is N, andX⁶ is N.

In some embodiments of Formula (IVk), X² is CH, X⁴ is CH, X⁵ is CH, andX⁶ is CR⁶.

In some embodiments, the compound of Formula (I) is a compound ofFormula (V):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (VI):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (VII):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (VIII):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (IX):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is the (S)-enantiomer of one of thepreceding compounds, or a pharmaceutically acceptable salt thereof. Insome embodiments, the compound is the (R)-enantiomer of one of thepreceding compounds, or a pharmaceutically acceptable salt thereof.

It is further appreciated that certain features of the presentdisclosure, which are, for clarity, described in the context of separateembodiments, can also be provided in combination in a single embodiment.Conversely, various features of the present disclosure, which are, forbrevity, described in the context of a single embodiment, can also beprovided separately or in any suitable subcombination. The presentdisclosure is intended to include all combinations of embodiments foreach variable described hereinabove including salts thereof.

At various places in the present specification, divalent linkingsubstituents are described. It is specifically intended that eachdivalent linking substituent include both the forward and backward formsof the linking substituent. For example, —NR(CR′R″)_(n)— includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR—. Where the structure clearlyrequires a linking group, the Markush variables listed for that groupare understood to be linking groups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. The substituents are independently selected, andsubstitution may be at any chemically accessible position. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substituent. A single divalent substituent, e.g., oxo, canreplace two hydrogen atoms. It is to be understood that substitution ata given atom is limited by valency.

As used herein, the phrase “each ‘variable’ is independently selectedfrom” means substantially the same as wherein “at each occurrence‘variable’ is selected from.”

Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₃, C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl,tert-butyl, isobutyl, sec-butyl; higher homologs such as2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl,and the like. In some embodiments, the alkyl group contains from 1 to 6carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkoxy”, employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2 fused rings). The term “C_(n-m)aryl” refers to an aryl group having from n to m ring carbon atoms.

Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl,indanyl, indenyl, and the like. In some embodiments, aryl groups havefrom 6 to 10 carbon atoms. In some embodiments, the aryl group is phenylor naphthyl. In some embodiments, the aryl is phenyl.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, ahalo is F, Cl, or Br. In some embodiments, a halo is F or Cl. In someembodiments, a halo is F. In some embodiments, a halo is Cl.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. Example haloalkoxy groupsinclude OCF₃ and OCHF₂. In some embodiments, the haloalkoxy group isfluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkoxycarbonylamino” refers to a groupof formula —NHC(O)O(C_(n-m) alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group has,independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “cyano-C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-CN.

As used herein, the term “HO—C₁₋₆ alkyl” refers to a group of formula—(C₁₋₆ alkylene)-OH.

As used herein, the term “HO—C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-OH.

As used herein, the term “C₁₋₆ alkoxy-C₁₋₆ alkyl” refers to a group offormula —(C₁₋₆ alkylene)-O(C₁₋₆ alkyl).

As used herein, the term “C₁₋₃ alkoxy-C₁₋₃ alkyl” refers to a group offormula —(C₁₋₃ alkylene)-O(C₁₋₃ alkyl).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonyloxy” refers to a group of formula—OC(O)NH₂.

As used herein, the term “C₁₋₃ alkylcarbonyloxy” refers to a group offormula —OC(O)(C₁₋₃ alkyl).

As used herein, the term “C₁₋₃ alkylaminocarbonyloxy” refers to a groupof formula —OC(O)NH(C₁₋₃ alkyl).

As used herein, the term “di(C₁₋₃ alkyl)aminocarbonyloxy” refers to agroup of formula —OC(O)N(C₁₋₃ alkyl)₂, wherein the two alkyl groups eachhas, independently, 1 to 3 carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2 fused rings) groups,spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group).

Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo or thienyl derivatives of cyclobutane, cyclopentane,cyclohexane, and the like. A cycloalkyl group containing a fusedaromatic ring can be attached through any ring-forming atom including aring-forming atom of the fused aromatic ring. Cycloalkyl groups can have3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (i.e., C₃₋₁₀). In someembodiments, the cycloalkyl is a C₃₋₁₀ monocyclic or bicycliccycloalkyl. In some embodiments, the cycloalkyl is a C₃₋₁₀ monocycliccycloalkyl which is optionally substituted by CH₂F, CHF₂, CF₃, andCF₂CF₃. In some embodiments, the cycloalkyl is a C₃₋₇ monocycliccycloalkyl. In some embodiments, the cycloalkyl is a C₄₋₇ monocycliccycloalkyl. In some embodiments, the cycloalkyl is a C₄₋₁₀ spirocycle orbridged cycloalkyl (e.g., a bridged bicycloalkyl group). Examplecycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane,bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, andthe like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g.,having 2 fused rings) aromatic heterocycle having at least oneheteroatom ring member selected from N, O, S and B, wherein any ringforming N is optionally an N-oxide group. In some embodiments, theheteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independentlyselected from N, O, S and B. In some embodiments, any ring-forming N ina heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having1, 2, 3, or 4 heteroatom ring members independently selected from N, O,S and B. In some embodiments, the heteroaryl is a 5-10 memberedmonocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ringmembers independently selected from N, O, and S. In some embodiments,the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroarylhaving 1, 2, 3, or 4 heteroatom ring members independently selected fromN, O, S and B. In some embodiments, the heteroaryl is a 5-10 memberedmonocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ringmembers independently selected from N, O, and S. In some embodiments,the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatomring members independently selected from N, O, S and B. In someembodiments, the heteroaryl is a 5-6 monocyclic heteroaryl ring having 1or 2 heteroatom ring members independently selected from N, O or S. Insome embodiments, the heteroaryl group contains 3 to 10, 4 to 10, 3 to7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroarylgroup has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-formingheteroatoms, 1 to 2 ring-forming heteroatoms or 1 ring-formingheteroatom. When the heteroaryl group contains more than one heteroatomring member, the heteroatoms may be the same or different. Exampleheteroaryl groups include, but are not limited to, pyridine, pyrimidine,pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, isoxazole,thiophene, thiazole, isothiazole, imidazole, furan, thiophene, triazole,tetrazole, thiadiazole, quinoline, isoquinoline, indole, benzothiophene,benzofuran, benzisoxazole, imidazo[1, 2-b]thiazole, purine, triazine,thieno[3,2-b]pyridine, imidazo[1,2-a]pyridine, 1,5-naphthyridine,1H-pyrazolo[4,3-b]pyridine, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl,1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl,1,3,4-oxadiazolyl, 1,2-dihydro-1,2-azaborine, and the like.

As used herein, “heterocycloalkyl” refers to monocyclic or polycyclicheterocycles having at least one non-aromatic ring (saturated orpartially unsaturated ring), wherein one or more of the ring-formingcarbon atoms of the heterocycloalkyl is replaced by a heteroatomselected from N, O, S and B, and wherein the ring-forming carbon atomsand heteroatoms of the heterocycloalkyl group can be optionallysubstituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), orS(O)₂, etc.). Heterocycloalkyl groups include monocyclic and polycyclic(e.g., having 2 fused rings) systems. Included in heterocycloalkyl aremonocyclic and polycyclic 3-10-, 4-10-, 3-7-, 4-7-, and 5-6-memberedheterocycloalkyl groups. Heterocycloalkyl groups can also includespirocycles and bridged rings (e.g., a 5-10 membered bridgedbiheterocycloalkyl ring having one or more of the ring-forming carbonatoms replaced by a heteroatom independently selected from N, O, S andB). The heterocycloalkyl group can be attached through a ring-formingcarbon atom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the non-aromatic heterocyclic ring, for example, benzo orthienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. In some embodiments, the heterocycloalkyl group contains3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments,the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1to 2 heteroatoms or 1 heteroatom. In some embodiments, theheterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1or 2 heteroatoms independently selected from N, O, S and B and havingone or more oxidized ring members.

Example heterocycloalkyl groups include pyrrolidin-2-one,1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl,morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl,isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, azepanyl, benzazapene, 1,2,3,4-tetrahydroisoquinoline,azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl,oxabicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl,diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl,diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl,diazabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl,azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl,oxa-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl,oxa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl,azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl,azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl,oxa-diazaspiro[4.4]nonanyl and the like.

As used herein, “C_(o-p) cycloalkyl-C_(n-m) alkyl-” refers to a group offormula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbonatoms and the alkylene linking group has n to m carbon atoms.

As used herein “C_(o-p) aryl-C_(n-m) alkyl-” refers to a group offormula aryl-alkylene-, wherein the aryl has o to p carbon atoms and thealkylene linking group has n to m carbon atoms.

As used herein, “heteroaryl-C_(n-m) alkyl-” refers to a group of formulaheteroaryl-alkylene-, wherein alkylene linking group has n to m carbonatoms.

As used herein “heterocycloalkyl-C_(n-m) alkyl-” refers to a group offormula heterocycloalkyl-alkylene-, wherein alkylene linking group has nto m carbon atoms.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

As used herein, the term “oxo” refers to an oxygen atom (i.e., ═O) as adivalent substituent, forming a carbonyl group when attached to a carbon(e.g., C═O or C(O)), or attached to a nitrogen or sulfur heteroatomforming a nitroso, sulfinyl or sulfonyl group.

As used herein, the term “independently selected from” means that eachoccurrence of a variable or substituent are independently selected ateach occurrence from the applicable list.

As used herein, a dashed bond (- - -) represents a single or double bonddepending on the nature of the atoms in each ring and as required tocomplete the valencies of the atoms being linked by the bond.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present disclosure. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration. The Formulas (e.g.,Formula (I), (II), etc.) provided herein include stereoisomers of thecompounds.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asj-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, enamine—imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

In some embodiments, the term “about” refers to plus or minus 10% of thevalue described. A skilled person in the art would know that the valuespresented herein can vary due to the conditions of the experiments suchas variability in data collection or instruments.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. The present disclosure also includespharmaceutically acceptable salts of the compounds described herein. Asused herein, “pharmaceutically acceptable salts” refers to derivativesof the disclosed compounds wherein the parent compound is modified byconverting an existing acid or base moiety to its salt form. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts of the present disclosureinclude the conventional non-toxic salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present disclosure can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

Synthesis

As will be appreciated by those skilled in the art, the compoundsprovided herein, including salts and stereoisomers thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

Compounds of Formula (I) can be prepared as shown in Scheme 1.Appropriately substituted starting materials 1-1 wherein Y^(B) is ahalogen (e.g., Cl, Br or I) can be converted to an appropriatelysubstituted metal 1-2 (e.g., M^(B) is B(OH)₂, Bpin, BF₃K, Sn(Bu)₃, orZn) under standard conditions (e.g., in the presence of a diboronreagent such as bis(pinacolato)diboron, a palladium catalyst, such asdichloro[bis(triphenylphosphoranyl)]palladium or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane, and a base, such as potassium acetate).Intermediate 1-3 wherein Y^(A) is a halogen (e.g., Cl, Br or I) orpseudohalogen (e.g., OMs or OTf) can be coupled with 1-2 under standardSuzuki conditions (e.g., in the presence of a palladium catalyst, suchas tetrakis(triphenylphosphine)palladium(0),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane orbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)and a base (e.g., a carbonate base such as potassium carbonate, orcesium fluoride)) or standard Stille conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)) to giveintermediate 1-4. Intermediate 1-4 can be converted to compound 1-5wherein yl is a halogen (e.g., Cl, Br or I) by treatment with a suitablehalogenating reagent such as an N-halosuccinimide (e.g.,N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide). Compound1-5 can be coupled with R¹-M, where M is a boronic acid, boronate ester,potassium trifluoroborate, or an appropriately substituted metal such asSn(Bu)₃ or Zn, under standard Suzuki conditions (e.g., in the presenceof a palladium catalyst, such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane orbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)and a base (e.g., a carbonate base such as potassium carbonate, orcesium fluoride)) or standard Stille conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)) to affordcompounds of Formula (I).

Alternatively, intermediate 1-6 wherein Y¹ and Y^(A) are independentlyhalogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OMs or OTf) can becoupled with a suitable metal 1-2 under standard Suzuki conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane orbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)and a base (e.g., a carbonate base or cesium fluoride)) or standardStille conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to givecompound 1-5, which is useful in the preparation of compounds of Formula(I) by coupling with R¹-M as described above.

Beginning with a suitably substituted starting material 1-6, wherein Y¹and Y^(A) are independently halogen (e.g., Cl, Br or I) or pseudohalogen(e.g., OMs or OTf), the order of steps can be reversed as shown inScheme 1, so that cross-coupling with an appropriately substituted metalR¹-M is performed as described above prior to coupling of 1-2, to yieldintermediate 1-9. This can be followed by cross coupling withintermediate 1-2 as described above, to provide compounds of Formula(I).

Where desired, appropriately substituted starting material 1-7, whereinY is a halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OMs or OTf)can be coupled with R¹-M, where M is a boronic acid, boronate ester,potassium trifluoroborate, or an appropriately substituted metal such asSn(Bu)₃ or Zn, under standard Suzuki conditions (e.g., in the presenceof a palladium catalyst, such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane orbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)and a base (e.g., a carbonate base or cesium fluoride)) or standardStille conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)) to affordintermediate 1-8. Intermediate 1-8 can be converted to intermediate 1-9wherein Y^(A) is a halogen (e.g., Cl, Br or I) by treatment with asuitable halogenating reagent such as an N-halosuccinimide (e.g.,N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide).Intermediate 1-9 can be converted to compounds of Formula (I) via crosscoupling with an appropriately substituted metal 1-2 as described above.

Appropriately substituted starting materials are commercially availableor can be synthesized based on the general procedures described in theart, e.g., in International Patent Application Publication Nos.:WO2011008487, WO2011075643, WO2011075630, WO2011130342, WO2013033569,WO2016130501, and WO2017223414, the disclosure of each of which isincorporated herein by reference in its entirety.

Compounds of Formula (IIo) can be prepared as shown in Scheme 2.Appropriately substituted benzoate ester 2-1 (e.g., R is —CH₃, —CH₂CH₃and the like) wherein Y^(B) is a halo (e.g., Cl, Br, or I) or pseudohalogroup (e.g., OTf or OMs), Y⁶ is a suitable halogen (e.g. Cl, Br or I),and substituent X¹¹ is a suitable alkyl group, can be halogenated bytreatment with a halogenating reagent such as an N-halosuccinimide(e.g., N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide) toafford intermediate 2-3 wherein L¹¹ is a halogen (e.g., Cl, Br or I).Alternatively, a suitably substituted starting material 2-2 bearing analcohol substituent on X¹¹ can be halogenated by treatment with asuitable halogenating reagent (e.g., SOCl₂ or triphenylphosphinedibromide) to afford 2-3. Alternatively, 2-2 can be treated with asulfonyl chloride (e.g., p-toluenesulfonyl chloride or methanesulfonylchloride) in the presence of a base (e.g., triethylamine or Hunig'sbase) to afford 2-3 wherein L¹¹ is a leaving group (e.g., OMs or OTs).Intermediate 2-3 can be converted to intermediate 2-4 via reaction withan amine (R¹⁰NH₂) in the presence of acid (e.g., boric acid) and base(e.g., a carbonate base such as K₂CO₃, Cs₂CO₃ or Na₂CO₃). Intermediate2-4 wherein Y⁶ is a suitable halogen (e.g., Cl, Br or I) can beconverted to thioether 2-5 by heating in the presence of a suitablesulfur nucleophile R^(b6)SM wherein M is a suitable metal such as sodium(e.g., sodium methanethiolate). Oxidation of intermediate 2-5 with asuitable oxidizing agent (e.g., m-CPBA) can provide sulfone intermediate2-6. The Y^(B) halo (e.g., Cl, Br, or I) or pseudohalo group (e.g., OTfor OMs) of intermediate 2-6 can be converted to an appropriatelysubstituted metal (e.g., M^(B) is B(OH)₂, Bpin, BF₃K, Sn(Bu)₃, or Zn)under standard conditions (e.g., in the presence of a diboron reagentsuch as bis(pinacolato)diboron, a palladium catalyst, such asdichloro[bis(triphenylphosphoranyl)]palladium or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane, and a base, such as potassium acetate) to affordcompound 2-7. Intermediate 2-7 can be used as shown in Scheme 1 toprepare compounds of Formula (IIo).

Compounds of Formula (IIo) can be prepared as shown in Scheme 3. Asuitably substituted intermediate 3-1 wherein Y^(B) and Y⁶ areindependently halogen (e.g., Cl, Br, or I) or pseudohalo group (e.g.,OTf or OMs) can be converted to an appropriate substituted metal 3-2(e.g., M^(B) is B(OH)₂, Bpin, BF₃K, Sn(Bu)₃, or Zn) under standardconditions (e.g., in the presence of a diboron reagent such asbis(pinacolato)diboron, a palladium catalyst, such asdichloro[bis(triphenylphosphoranyl)]palladium or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane, and a base, such as potassium acetate).Intermediate 3-2 can be transformed to compound 3-3 via the methodsshown in Scheme 1. Compound 3-3 wherein Y⁶ is a suitable halogen (e.g.,Cl, Br or I) can be converted to thioether 3-4 by heating in thepresence of a suitable sulfur nucleophile R^(b6)SM wherein M is asuitable metal such as sodium (e.g., sodium methanethiolate). Oxidationof compound 3-4 with a suitable oxidizing agent (e.g., m-CPBA) canprovide compounds of Formula (IIo).

Compounds of Formula (IIp) can be prepared as shown in Scheme 4.Intermediate 4-1 wherein Y^(B) is a halogen (e.g., Cl, Br, or I) orpseudohalo group (e.g., OTf or OMs) can be converted to an appropriatelysubstituted metal 4-2 (e.g., M^(B) is B(OH)₂, Bpin, BF₃K, Sn(Bu)₃, orZn) under standard conditions (e.g., in the presence of a diboronreagent such as bis(pinacolato)diboron, a palladium catalyst, such asdichloro[bis(triphenylphosphoranyl)]palladium or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane, and a base, such as potassium acetate). In somecases, treatment of intermediate 4-2 with an alkylating agent R¹⁰-L,wherein L is a suitable leaving group (e.g., a halogen (e.g., Cl, Br, orI) or pseudohalo group (e.g., OTs or OMs)), in the presence of a base(e.g., sodium hydride or carbonate base (e.g., cesium carbonate)) canprovide intermediate 4-3. Alternatively, the steps can be performed inreverse order (i.e., 4-1 may be alkylated with R¹⁰-L under conditionsdescribed above, to provide compound 4-4, which can subsequentlyconverted to metal 4-3 under conditions described above) to affordintermediate 4-3, which can be converted to compounds of Formula (IIp)as outlined in Scheme 1.

Compounds of Formula (Ib) can be prepared as shown in Scheme 5. Suitablestarting materials 5-1 wherein Y¹ and Y^(A) are independently halogen(e.g., Cl, Br, or I) or pseudohalo group (e.g., OTf or OMs) can beselectively coupled to intermediate 5-2 wherein M^(B) is a boronic acid,boronate ester, potassium trifluoroborate, or an appropriatelysubstituted metal such as Sn(Bu)₃ or Zn, under standard Suzukiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane orbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)and a base (e.g., a carbonate base or cesium fluoride)) or standardStille conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to giveintermediate 5-3. Intermediate 5-3 can be converted to compounds ofFormula (Ib) wherein R¹ is an amide via Pd-mediated carbonylation. Forexample, intermediate 5-3 wherein Y¹ is a suitable halogen (e.g., Cl, Bror I) or pseudohalo group (e.g., OTf or OMs) can be converted to anamide by reacting with CO gas in the presence of a suitable amineR^(1a)R^(1b)NH and a palladium catalyst (e.g.,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium). Alternatively,the Pd-mediated carbonylation can be carried out in the absence of anamine and in a suitable alcohol solvent, ROH (e.g., R═-CH₃ or —CH₂CH₃)to provide an ester 5-4, which can be hydrolyzed to a carboxylic acid5-5 under standard conditions (e.g., LiOH). The carboxylic acid 5-5 canbe coupled with amine R^(c1)R^(d1)NH under standard amide couplingconditions (e.g., HATU or EDCI in the presence of a base such astriethylamine or Hunig's base) to afford amide compounds of Formula(Ib). Alternatively, ester 5-4 can be converted to compounds of Formula(Ib) wherein R¹ is an amide by reacting the ester 5-4 with an amineR^(c1)R^(d1)NH in the presence of a lewis acid (e.g., AlMe₃).

Compounds of Formula (Ib) wherein R¹ is an amide can be prepared asshown in Scheme 6. Suitable carboxylic acid starting material 6-1 can becoupled with an amine R^(c1)R^(d1)NH under standard amide couplingconditions (e.g., HATU or EDCI in the presence of a base such astriethylamine or Hunig's base) to afford intermediate 6-2. Intermediate6-2 wherein Y^(A) is a halogen (e.g., Cl, Br, or I) or pseudohalo group(e.g., OTf or OMs) can be coupled to intermediate 6-3 where M^(B) is aboronic acid, boronate ester, potassium trifluoroborate, or anappropriately substituted metal such as Sn(Bu)₃ or Zn, under standardSuzuki conditions (e.g., in the presence of a palladium catalyst, suchas tetrakis(triphenylphosphine)palladium(0),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane orbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)and a base (e.g., a carbonate base or cesium fluoride)) or standardStille conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)) to givecompounds of Formula (Ib).

Compounds of the Formula IIq can be prepared as shown in Scheme 7.Heteroaromatic bicyclic starting materials 7-1 (wherein Y^(B) is Cl, Br,or I) can be alkylated with electrophiles R-L (wherein L=a leaving groupsuch as Br, I, OSO₂Me, etc.) utilizing a base (e.g., K₂CO₃) in asuitable solvent such as DMF or MeCN. Alkylation can also beaccomplished with alcohols R—OH under Mitsunobu conditions (e.g., PPh₃,DEAD). Alkylated derivatives 7-2 can subsequently be converted tocompounds of the Formula IIq by the methods outlined in Scheme 1.

Compounds of the Formula (IIr) can also be synthesized as shown inScheme 8. Amino containing starting materials 8-1 wherein X¹¹=aheteroatom (e.g., N, O, S) can undergo cyclization upon treatment withan ester or acid halide 8-2 (wherein Z═Cl, Br, OR, etc.) to affordbicyclic derivatives 8-3, which can subsequently be converted tocompounds of the Formula (IIr) by the methods outlined in Scheme 1.

Compounds of the Formula (IVj) can also be synthesized as shown inScheme 9. Treatment of amino containing starting materials 9-1 with anaminating reagent H₂N—OZ (9-2, wherein Z is a leaving group such asSO₃H, 2,4-dinitrophenyl, etc.) affords the aminated derivatives 9-3.Reaction with aldehydes 9-4 and a base such as DBU results incyclization to afford triazoles 9-5, which can subsequently be convertedto compounds of the Formula (IVj) by the methods outlined in Scheme 1.

Compounds of the Formula (IVk) can also be prepared as shown in Scheme10.

Treatment of amino containing starting materials 10-1 with an α-haloketone 10-2 at elevated temperature results in cyclization to provideimidazolo-fused derivatives 10-3. In turn, these intermediates cansubsequently be converted to compounds of the Formula (IVk) by themethods outlined in Scheme 1.

Compounds of the Formula (IIIi) can also be prepared as shown in Scheme11. Treatment of amino containing starting materials 11-1 with anaminating reagent H₂N—OZ (9-2, wherein Z is a leaving group such asSO₃H, 2,4-dinitrophenyl, etc.) affords the aminated derivatives 11-2.Reaction with alkynoates 11-3 results in cyclization to providepyrazolo-fused products 11-4. The amino group in 11-4 can undergodiazotization (e.g., NaNO₂, t-BuNO₂, etc.) followed by displacement witha halogen utilizing a copper (I) source such as CuBr to affordintermediates 11-5. Heating under aqueous acidic conditions providesdecarboxylated products 11-6, which can subsequently be converted tocompounds of the Formula (IIIi) by the methods outlined in Scheme 1.

Compounds of the Formula (IIIj) can also be prepared as shown in Scheme12. Reaction of 2-aminopyrazoles 12-1 with 3-alkoxyacrylates 12-2affords pyridones 12-3. Deoxyhalogenation can be achieved with adehydrating agent such as SOCl₂ or triphenylphosphine dibromide toprovide the halogenated derivatives 12-4, which can subsequently beconverted to compounds of the Formula (IIIj) by the methods outlined inScheme 1.

The reactions for preparing compounds described herein can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,(e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature). A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

The expressions, “ambient temperature” or “room temperature” or “rt” asused herein, are understood in the art, and refer generally to atemperature, e.g., a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Preparation of compounds described herein can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., Wiley &Sons, Inc., New York (1999).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) and normal phase silicachromatography.

Methods of Use

The compounds, salts or stereoisomers thereof described herein inhibitactivity of PI3Kγ kinase. Accordingly, the compounds, salts orstereoisomers described herein can be used in methods of inhibitingPI3Kγ kinase by contacting the kinase with any one or more of thecompounds, salts, or compositions described herein. In some embodiments,the compounds or salts can be used in methods of inhibiting activity ofPI3Kγ in an individual/patient in need of the inhibition byadministering an effective amount of a compound or salt of describedherein. In some embodiments, modulating is inhibiting. In someembodiments, the contacting is in vivo. In some embodiments, thecontacting is ex vivo. Advantageously, the compounds as described hereindemonstrate better efficacy and favorable safety and toxicity profilesin animal studies.

In some embodiments, the PI3Kγ includes a mutation. A mutation can be areplacement of one amino acid for another, or a deletion of one or moreamino acids. In such embodiments, the mutation can be present in thekinase domain of the PI3Kγ.

In some embodiments, the compound or salt further inhibits PI3Kδ.

The compounds or salts described herein can be selective. By “selective”is meant that the compound binds to or inhibits PI3Kγ with greateraffinity or potency, respectively, compared to at least one otherkinase. In some embodiments, the compounds of the disclosure areselective inhibitors of PI3Kγ over PI3Kδ, PI3Kα, and PI3Kβ. In someembodiments, the compounds of the disclosure are selective inhibitors ofPI3Kγ over PI3Kα and PI3Kβ. In some embodiments, selectivity can be atleast about 2-fold, 3-fold, 5-fold, 10-fold, at or 20-fold over PI3Kδ asmeasured by the assays described herein. In some embodiments,selectivity can be tested at the 2 μM ATP concentration of each enzyme.In some embodiments, the selectivity of compounds of the disclosure canbe determined by cellular assays associated with particular PI3K kinaseactivity.

Another aspect of the present disclosure pertains to methods of treatinga kinase PI3Kγ-associated disease or disorder in an individual (e.g.,patient) by administering to the individual in need of such treatment atherapeutically effective amount or dose of one or more compounds of thepresent disclosure or a pharmaceutical composition thereof. API3Kγ-associated disease or disorder can include any disease, disorderor condition that is directly or indirectly linked to expression oractivity of the PI3Kγ, including overexpression and/or abnormal activitylevels.

In some embodiments, the disease or disorder is an autoimmune disease ordisorder, cancer, cardiovascular disease, or neurodegenerative disease.

In some embodiments, the disease or disorder is lung cancer (e.g.,non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer,head and neck squamous cell carcinoma, prostate cancer, liver cancer,color cancer, endometrial cancer, bladder cancer, skin cancer, cancer ofthe uterus, renal cancer, gastric cancer, or sarcoma. In someembodiments, the sarcoma is Askin's tumor, sarcoma botryoides,chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma,malignant schwannoma, osteosarcoma, alveolar soft part sarcoma,angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans,desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma,extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma,gastrointestinal stromal tumor (GIST), hemangiopericytoma,hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma,lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheathtumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, orundifferentiated pleomorphic sarcoma.

In some embodiments, the disease or disorder is mesothelioma oradrenocarcinoma. In some embodiments, the disease or disorder ismesothelioma. In some embodiments, the disease or disorder isadrenocarcinoma.

In some embodiments, the disease or disorder is acute myeloid leukemia(e.g., acute monocytic leukemia), small lymphocyctic lymphoma, chroniclymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiplemyeloma, T-cell actute lymphoblasic leukemia (T-ALL), cutaneous T-celllymphoma, large granular lymphocytic leukemia, mature (peripheral)t-cell neoplasm (PTCL), anaplastic large cell lymphoma (ALCL), orlymphoblastic lymphoma. In some embodiments, the mature (peripheral)t-cell neoplasm (PTCL) is T-cell prolymphocytic leukemia, T-cellgranular lymphocytic leukemia, aggressive NK-cell leukemia, mycosisfungoides/Sezary syndrome, naplastic large cell lymphoma (T-cell type),enteropathy type T-cell lymphoma, adult T-cell leukemia/lymphoma, orangioimmunoblastic T-cell lymphoma In some embodiments, the anaplasticlarge cell lymphoma (ALCL) is systemic ALCL or primary cutaneous ALCL.

In some embodiments, the disease or disorder is Burkitt's lymphoma,acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin'slymphoma, Hodgkin's lymphoma, hairy cell leukemia, Mantle cell lymphoma,small lymphocytic lymphoma, follicular lymphoma, xenoderoma pigmentosum,keratoctanthoma, lymphoplasmacytic lymphoma, extranodal marginal zonelymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia,acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatictissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma,lymphomatoid granulomatosis, splenic marginal zone lymphoma, primaryeffusion lymphoma, intravascular large B-cell lymphoma, plasma cellleukemia, extramedullary plasmacytoma, smouldering myeloma (akaasymptomatic myeloma), monoclonal gammopathy of undeterminedsignificance (MGUS), or diffuse large B cell lymphoma.

In some embodiments, the disease or disorder is Burkitt's lymphoma,acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin'slymphoma, Hodgkin's lymphoma, hairy cell leukemia, Mantle cell lymphoma,small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacyticlymphoma, extranodal marginal zone lymphoma, Waldenstrom'smacroglobulinemia, prolymphocytic leukemia, acute lymphoblasticleukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT)lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoidgranulomatosis, splenic marginal zone lymphoma, primary effusionlymphoma, intravascular large B-cell lymphoma, plasma cell leukemia,extramedullary plasmacytoma, smouldering myeloma (aka asymptomaticmyeloma), monoclonal gammopathy of undetermined significance (MGUS), ordiffuse large B cell lymphoma.

MDSC (myeloid-derived suppressor cells) are a heterogenous group ofimmune cells from the myeloid lineage (a family of cells that originatefrom bone marrow stem cells). MDSCs strongly expand in pathologicalsituations such as chronic infections and cancer, as a result of analtered haematopoiesis. MDSCs are discriminated from other myeloid celltypes in which they possess strong immunosuppressive activities ratherthan immunostimulatory properties. Similar to other myeloid cells, MDSCsinteract with other immune cell types including T cells, dendriticcells, macrophages and natural killer cells to regulate their functions.In some embodiments, the compounds, etc. described herein can be used inmethods realted to cancer tissue (e.g., tumors) with high infiltrationof MDSCs, including Solid tumors with high basal level of macrophageand/or MDSC infiltration.

In some embodiments, the non-Hodgkin's lymphoma (NHL) is relapsed NHL,refractory NHL, recucurrent follicular NHL, indolent NHL (iNHL), oraggressive NHL (aNHL).

In some embodiments, the diffuse large B cell lymphoma is activatedB-cell like (ABC) diffuse large B cell lymphoma, or germinal center Bcell (GCB) diffuse large B cell lymphoma. In some embodiments, theBurkitt's lymphoma is endemic Burkitt's lymphoma, sporadic Burkitt'slymphoma, or Burkitt's-like lymphoma.

In some embodiments, the disease or disorder is rheumatoid arthritis,multiple sclerosis, systemic lupus erythematous, asthma, allergy (e.g,allergic rhinitis), pancreatitis, psoriasis, anaphylaxis,glomerulonephritis, inflammatory bowel disease (e.g., Crohn's diseaseand ulcerative colitis), thrombosis, meningitis, encephalitis, diabeticretinopathy, benign prostatic hypertrophy, myasthenia gravis, Sjögren'ssyndrome, osteoarthritis, restenosis, or atherosclerosis.

In some embodiments, the disease or disorder is heart hypertropy,cardiac myocyte dysfunction, acute coronary syndrome, chronicobstructive pulmonary disease (COPD), chronic bronchitis, elevated bloodpressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia(e.g., hemolytic anemia, aplastic anemia, or pure red cell anemia),bacterial infection, viral infection, graft rejection, kidney disease,anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal musclehypertrophy, angiogenesis, sepsis, graft-versus-host disease, allogeneicor xenogeneic transplantation, glomerulosclerosis, progressive renalfibrosis, idiopathic thrombocytopenic purpura (ITP), idiopathicpulmonary fibrosis, autoimmune hemolytic anemia, vasculitis, lupusnephritis, pemphigus, or membranous nephropathy.

In some embodiments, disease or disorder is heart hypertropy, cardiacmyocyte dysfunction, chronic obstructive pulmonary disease (COPD),elevated blood pressure, ischemia, ischemia-reperfusion,vasoconstriction, anemia (e.g., hemolytic anemia, aplastic anemia, orpure red cell anemia), bacterial infection, viral infection, graftrejection, kidney disease, anaphylactic shock fibrosis, skeletal muscleatrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graftrejection, glomerulosclerosis, progressive renal fibrosis, idiopathicthrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis,systemic lupus erythematosus, lupus nephritis, pemphigus, or membranousnephropathy.

In some embodiments, the disease or disorder is Alzheimer's disease,central nervous system trauma, or stroke.

In some embodiments, the idiopathic thrombocytopenic purpura (ITP) isrelapsed ITP or refractory ITP.

In some embodiments, the vasculitis is Behcet's disease, Cogan'ssyndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu'sarteritis, Buerger's disease (thromboangiitis obliterans), centralnervous system vasculitis, Kawasaki disease, polyarteritis nodosa,Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis (essential orhepatitis C virus (HCV)-induced), Henoch-Schonlein purpura (HSP),hypersensitivity vasculitis, microscopic polyangiitis, Wegener'sgranulomatosis, or anti-neutrophil cytoplasm antibody associated (ANCA)systemic vasculitis (AASV).

The present disclosure further provides a compound described herein, ora pharmaceutically acceptable salt thereof, for use in any of themethods described herein.

The present disclosure further provides use of a compound describedherein, or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament for use in any of the methods describedherein.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a PI3K with a compound of the disclosure includesthe administration of a compound of the present disclosure to anindividual or patient, such as a human, having a PI3K, as well as, forexample, introducing a compound of the disclosure into a samplecontaining a cellular or purified preparation containing the PI3K.

It is believed that compounds of provdied herein (e.g., compounds ofFormula (I), or pharmaceutically acceptable salts thereof) or any of theembodiments thereof, may possess satisfactory pharmacological profileand promising biopharmaceutical properties, such as toxicologicalprofile, metabolism and pharmacokinetic properties, solubility, andpermeability. It will be understood that determination of appropriatebiopharmaceutical properties is within the knowledge of a person skilledin the art, e.g., determination of cytotoxicity in cells or inhibitionof certain targets or channels to determine potential toxicity.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” can refer to one ormore of (1) inhibiting the disease; for example, inhibiting a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., arresting further development of the pathology and/orsymptomatology); and (2) ameliorating the disease; for example,ameliorating a disease, condition or disorder in an individual who isexperiencing or displaying the pathology or symptomatology of thedisease, condition or disorder (i.e., reversing the pathology and/orsymptomatology) such as decreasing the severity of disease.

In some embodiments, the compounds of the present disclosure are usefulin preventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

I. Immune-checkpoint therapies

In some embodiments, the PI3Kγ inhibitors provided herein can be used incombination with one or more immune checkpoint inhibitors for thetreatment of cancer as described herein. In one embodiment, thecombination with one or more immune checkpoint inhibitors as describedherein can be used for the treatment of melanoma. Compounds of thepresent disclosure can be used in combination with one or more immunecheckpoint inhibitors. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CD20, CD28, CD40,CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM,arginase, HPK1, CD137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA,CTLA-4, LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1 and PD-L2. In someembodiments, the immune checkpoint molecule is a stimulatory checkpointmolecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. Insome embodiments, the immune checkpoint molecule is an inhibitorycheckpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO,KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, thecompounds of the disclosure provided herein can be used in combinationwith one or more agents selected from KIR inhibitors, TIGIT inhibitors,LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR betainhibitors.

In some embodiments, the PI3Kγ inhibitors provided herein can be used incombination with one or more agonists of immune checkpoint molecules,e.g., OX40, CD27, OX40, GITR, and CD137 (also known as 4-1BB).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®),pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. Insome embodiments, the anti-PD-1 monoclonal antibody is nivolumab orpembrolizumab. In some embodiments, the anti-PD1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody isMGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Otheranti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g.urelumab, utomilumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MED14736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MED14736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1 monoclonalantibody. In some embodiments, the anti-PD-1/PD-L1 is MCLA-136.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916,PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40Lfusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

In some embodiments, the PI3Kγ inhibitors provided herein can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

II. Cancer Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors or one or moretherapies for the treatment of diseases, such as cancer. Examples ofdiseases and indications treatable with combination therapies includethose as described herein. Examples of cancers include solid tumors andliquid tumors, such as blood cancers.

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors,chemokine receptor inhibitors, and phosphatase inhibitors, as well astargeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET,VEGFR, PDGFR, c-Kit, IGF-1R, RAF, and FAK kinase inhibitors such as, forexample, those described in WO 2006/056399. Other agents such astherapeutic antibodies can be used in combination with the compounds ofthe present disclosure for treatment of PI3K-associated diseases,disorders or conditions. The one or more additional pharmaceuticalagents can be administered to a patient simultaneously or sequentially.

For example, the compounds as disclosed herein can be combined with oneor more inhibitors of the following kinases for the treatment of cancerand other diseases or disorders described herein: Akt1, Akt2, Akt3,TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK,MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFaR,PDGF(3R, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2,FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4,EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak,SYK, FRK, JAK, ABL, ALK and B-Raf Non-limiting examples of inhibitorsthat can be combined with the compounds of the present disclosure fortreatment of cancer and other diseases and disorders described hereininclude an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g.,INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2,e.g., ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g.,epacadostat, NLG919, or BMS-986205), an LSD1 inhibitor (e.g., INCB59872and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797and INCB50465), a Pim inhibitor, a CSF1R inhibitor, a TAM receptortyrosine kinases (Tyro-3, Axl, and Mer), a histone deacetylase inhibitor(HDAC) such as an HDAC8 inhibitor, an angiogenesis inhibitor, aninterleukin receptor inhibitor, bromo and extra terminal family membersinhibitors (for example, bromodomain inhibitors or BET inhibitors suchas INCB54329 and INCB57643) and an adenosine receptor antagonist orcombinations thereof.

In some embodiments, the compound or salt described herein isadministered with a PI3Kδ inhibitor. In some embodiments, the compoundor salt described herein is administered with a JAK inhibitor. In someembodiments, the compound or salt described herein is administered witha JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In someembodiments, the compound or salt described herein is administered witha JAK1 inhibitor. In some embodiments, the compound or salt describedherein is administered with a JAK1 inhibitor, which is selective overJAK2.

Example antibodies for use in combination therapy include but are notlimited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A),Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g.anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) andantibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present disclosure and are presented as a non-limitinglist: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662,IRESSA™(gefitinib), TARCEVA™ (erlotinib), antibodies to EGFR, intron,ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine,ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine,6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™(oxaliplatin), pentostatine, vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase,teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,estramustine, medroxyprogesteroneacetate, leuprolide, flutamide,toremifene, goserelin, carboplatin, hydroxyurea, amsacrine,procarbazine, mitotane, mitoxantrone, levamisole, navelbene,anastrazole, letrazole, capecitabine, reloxafine, droloxafine,hexamethylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™(tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan),TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine,porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan,trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab,C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine,aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Smll,fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, andMDL-101,731.

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumortargeted therapy, adjuvanttherapy, immunotherapy, or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, Toll receptor agonists, STING agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor and the like. The compounds can be administered in combinationwith one or more anti-cancer drugs, such as a chemotherapeutics. Examplechemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide,asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib,bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral,calusterone, capecitabine, carboplatin, carmustine, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, dalteparin sodium, daunorubicin,decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel,doxorubicin, dromostanolone propionate, eculizumab, epirubicin,erlotinib, estramustine, etoposide phosphate, etoposide, exemestane,fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinibditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate,levamisole, lomustine, meclorethamine, megestrol acetate, melphalan,mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab,olaparib, oxaliplatin, paclitaxel, pamidronate, panitumumab,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pipobroman, plicamycin, procarbazine, quinacrine, rasburicase,rituximab, ruxolitinib, rucaparib, streptozocin, tamoxifen,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,vorinostat, niraparib, veliparib, talazoparib and zoledronate.

Additional examples of chemotherapeutics include proteosome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™),nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceuticallyacceptable salts. Other example suitable Bcr-Abl inhibitors include thecompounds, and pharmaceutically acceptable salts thereof, of the generaand species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S.Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib,linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib,crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and theirpharmaceutically acceptable salts. Other example suitable Flt-3inhibitors include compounds, and their pharmaceutically acceptablesalts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include dabrafenib, sorafenib, andvemurafenib, and their pharmaceutically acceptable salts. Other examplesuitable RAF inhibitors include compounds, and their pharmaceuticallyacceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062,VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptablesalts. Other example suitable FAK inhibitors include compounds, andtheir pharmaceutically acceptable salts, as disclosed in WO 04/080980,WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO01/014402.

In some embodiments, the compounds of the disclosure can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic in the treatment of cancer, and mayimprove the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). Additive or synergistic effects are desirableoutcomes of combining a PI3K inhibitor of the present disclosure with anadditional agent.

In some embodiments, the compounds of the disclosure can be used incombination with an inhibitor of JAK or PI3Kδ.

The agents can be combined with the present compound in a single orcontinuous dosage form, or the agents can be administered simultaneouslyor sequentially as separate dosage forms.

The compounds of the present disclosure can be used in combination withone or more other inhibitors or one or more therapies for the treatmentof infections. Examples of infections include viral infections,bacterial infections, fungus infections or parasite infections.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the compounds of thedisclosure where the dexamethasone is administered intermittently asopposed to continuously.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp 100, MAGEantigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected toexpress the cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

In some further embodiments, combinations of the compounds of thedisclosure with other therapeutic agents can be administered to apatient prior to, during, and/or after a bone marrow transplant or stemcell transplant. The compounds of the present disclosure can be used incombination with bone marrow transplant for the treatment of a varietyof tumors of hematopoietic origin.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with vaccines, to stimulate theimmune response to pathogens, toxins, and self antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas Aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses,echovirus, rhinovirus, coxsackie virus, cornovirus, respiratorysyncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus,parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus,molluscum virus, poliovirus, rabies virus, JC virus and arboviralencephalitis virus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the disclosure can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the disclosure, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the disclosure may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the disclosure can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.

The formulations can additionally include: lubricating agents such astalc, magnesium stearate, and mineral oil; wetting agents; emulsifyingand suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the disclosure can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the disclosure contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about 40 to about 45, or about 45 to about 50 mgof the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the disclosure.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentdisclosure can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the disclosure. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the disclosure in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of thedisclosure can be provided in an aqueous physiological buffer solutioncontaining about 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.

Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the disclosure can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present disclosure relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating PI3K in tissue samples,including human, and for identifying PI3K ligands by inhibition bindingof a labeled compound. Substitution of one or more of the atoms of thecompounds of the present disclosure can also be useful in generatingdifferentiated ADME (Adsorption, Distribution, Metabolism andExcretion). Accordingly, the present disclosure includes PI3K assaysthat contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula (I) can be optionally substituted with deuterium atoms, suchas -CD₃ being substituted for —CH₃). In some embodiments, alkyl groupsof the disclosed Formulas (e.g., Formula (I), (II), etc.), can beperdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. For example, one or more hydrogen atoms in acompound presented herein can be replaced or substituted by deuterium(e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group can be replacedby deuterium atoms, such as -CD₃ being substituted for —CH₃). In someembodiments, the compound includes two or more deuterium atoms. In someembodiments, the compound includes 1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8,or 1-9 deuterium atoms. In some embodiments, all of the hydrogen atomsin a compound can be replaced or substituted by deuterium atoms.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of any alkyl, alkenyl, alkynyl, aryl, phenyl,cycloalkyl, heterocycloalkyl, or heteroaryl substituents, or —C₁₋₆alkyl-, alkylene, alkenylene, and alkynylene linking groups, asdescribed herein, are each optionally replaced by a deuterium atom.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J Med. Chem. 2011, 54, 201-210; R. Xu et. al. JLabel Compd. Radiopharm. 2015, 58, 308-312). In particular, substitutionat one or more metabolism sites may afford one or more of thetherapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro PI3K labeling and competitionassays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I or ³⁵S canbe useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I,¹³¹I, ⁷⁵Br, ⁷⁶Br or 77Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the disclosure can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a PI3K by monitoring its concentrationvariation when contacting with the PI3K, through tracking of thelabeling. For example, a test compound (labeled) can be evaluated forits ability to reduce binding of another compound which is known to bindto a PI3K (i.e., standard compound). Accordingly, the ability of a testcompound to compete with the standard compound for binding to the PI3Kdirectly correlates to its binding affinity. Conversely, in some otherscreening assays, the standard compound is labeled and test compoundsare unlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, forexample, in the treatment or prevention of PI3K-associated diseases ordisorders, such as cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the disclosure. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to be PI3Kγinhibitors according to at least one assay described herein.

EXAMPLES

Preparatory LC-MS purifications of some of the compounds prepared wereperformed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature (see e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J Combi. Chem., 6, 874-883 (2004)).

The compounds separated were typically subjected to analytical liquidchromatography mass spectrometry (LCMS) for purity analysis under thefollowing conditions: Instrument=Agilent 1100 series, LC/MSD; Column:Waters Sunfire™ C₁₈ 5 m, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFAin water and mobile phase B: acetonitrile; gradient 2% to 80% B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

-   -   pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 30×100 mm or        Waters XBridge™ C1₈ 5 μm, 30×100 mm column, eluting with mobile        phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile        phase B: acetonitrile; the flow rate was 60 mL/minute, the        separating gradient was optimized for each compound using the        Compound Specific Method Optimization protocol as described in        the literature (see e.g., “Preparative LCMS Purification:        Improved Compound Specific Method Optimization”, K. Blom, B.        Glass, R. Sparks, A. Combs, J Comb. Chem., 6, 874-883 (2004)).

pH=6.5 purifications: Waters XBridge™ C₁₈ 5 μm, 30×100 mm column,eluting with mobile phase A: 100 mM ammonium acetate (NH₄OAc) in waterand mobile phase B: acetonitrile; the flow rate was 60 mL/minute, theseparating gradient was optimized for each compound using the CompoundSpecific Method Optimization protocol as described in the literature(see e.g. “Preparative LCMS Purification: Improved Compound SpecificMethod Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J Comb.Chem., 6, 874-883 (2004)).

pH=10 purifications: Waters XBridge™ C₁₈ 5 μm, 30×100 mm column, elutingwith mobile phase A: 0.1% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 60 mL/minute, the separating gradientwas optimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature (see e.g.,“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)).

Stereochemical Rationale

The Sharpless asymmetric dihydroxylation of olefins has been studiedextensively, and its basis as a model for enantioselectivity is wellestablished (Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G.A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.;Xu, D.; Zhang, X.-L. J Org. Chem., 1992, 57, 2768-2771; and Kolb, H. C.;VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev., 1994, 94, 2483-2547).Briefly, the application of AD-mix-α (containing (DHQ)₂-PHAL) in thedihydroxylation of prop-1-en-2-ylbenzene affords(S)-2-phenylpropane-1,2-diol. Application of AD-mix-3 (containing(DHQD)₂-PHAL) in the dihydroxylation of prop-1-en-2-ylbenzene affords(R)-2-phenylpropane-1,2-diol (Sharpless and Kolb, supra). Moreno-Doradoet al. extended the method to the trifluoromethyl case (e.g.,(3,3,3-trifluoroprop-1-en-2-yl)benzene affords(S)-3,3,3-trifluoro-2-phenylpropane-1,2-diol when treated with AD-mix-αand affords (R)-3,3,3-trifluoro-2-phenylpropane-1,2-diol when treatedwith AD-mix-β), and the stereochemical outcome was verified bysubsequent conversion to well known compounds whose specific rotationswere found to be in agreement with the literature values (Moreno-Dorado,F. J.; Guerra, F. M.; Ortega, M. J.; Zubia, E.; Massanet, G. M.Tetrahedron: Asymmetry, 2003, 14, 503-510). While not wishing to bebound by any one theory, in the dihydroxylations performed on vinylarenes in the examples, we expect to obtain the (S)-configuration withAD-mix-α and the (R)-configuration with AD-mix-β.

Example 1.(S)-3-Amino-6-(2-(1-cyclopropylethyl)-1-oxoisoindolin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamidetrifluoroacetate salt

Step 1. (S)-5-Bromo-2-(1-cyclopropylethyl)isoindolin-1-one

A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (1.00 g, 3.25 mmol,Ark Pharm, AK-26333), (S)-1-cyclopropylethan-1-amine (0.304 g, 3.57mmol, Aldrich 727245), and K₂CO₃ (0.898 g, 6.49 mmol) in acetonitrile(8.1 mL) in a microwave vial was sealed and heated at 120° C. in amicrowave oven for 30 minutes. The reaction mixture was filtered andsolvent was removed in vacuo. The product was purified via flashchromatography, eluting with a gradient of 0-25% EtOAc in hexanes, toafford product as a white solid (0.42 g, 46%). LCMS for C₁₃H₁₅BrNO(M+H)⁺: calculated m/z=280.0; found 280.0.

Step 2.(S)-2-(1-Cyclopropylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

(S)-5-Bromo-2-(1-cyclopropylethyl)isoindolin-1-one (0.421 g, 1.50 mmol)was combined with bis(pinacolato)diboron (0.572 g, 2.25 mmol), potassiumacetate (0.885 g, 9.02 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.074 g, 0.090 mmol) in dioxane (7.5 mL), andthe mixture was degassed. The reaction mixture was heated to 80° C. for3 hours. Upon cooling to room temperature, the mixture was diluted withEtOAc, filtered over Celite®, and concentrated. The product was purifiedvia flash chromatography, eluting with a gradient from 0-20% EtOAc inhexanes, to afford product as a light yellow solid (theoretical yieldassumed). LCMS for C₁₉H₂₇BNO₃ (M+H)⁺: calculated m/z=328.2; found 328.2.

Step 3.(S)-5-(5-Amino-6-chloropyrazin-2-yl)-2-(1-cyclopropylethyl)isoindolin-1-one

A degassed mixture of(S)-2-(1-cyclopropylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one(0.050 g, 0.15 mmol), 5-bromo-3-chloropyrazin-2-amine (32 mg, 0.15 mmol,Ark Pharm AK-25099), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (25 mg, 0.031 mmol) in THF (2 mL) and 1.0 M K₂CO₃(0.61 mL, 0.61 mmol) was heated in a microwave to 120° C. for 35minutes. Upon cooling, the reaction mixture was diluted with EtOAc andfiltered. The layers were separated and the organic layer was washedwith brine, dried over MgSO₄, filtered, and concentrated. The productwas purified via flash chromatography, eluting with a gradient from0-100% EtOAc in hexanes, to afford the title compound (0.040 g, 81%).LCMS for C₁₇H₁₈ClN₄₀ (M+H)⁺: calculated m/z=329.1; found 329.1.

Step 4.(S)-3-Amino-6-(2-(1-cyclopropylethyl)-1-oxoisoindolin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamidetrifluoroacetate salt

Tetrahydro-2H-pyran-4-amine (49 mg, 0.49 mmol, Combi-Blocks, AM-1004),triethylamine (0.068 mL, 0.49 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (9.9 mg, 0.012 mmol) were combined with asolution of(S)-5-(5-amino-6-chloropyrazin-2-yl)-2-(1-cyclopropylethyl)isoindolin-1-one(0.020 g, 0.061 mmol) in dioxane (2 mL) in a sealable vial.

Carbon monoxide was bubbled through the solution for five minutes, usinga needle as an outlet.

The outlet needle was removed, and the reaction mixture was heated at80° C. under an atmosphere of CO for 4 hours. Solvent was removed invacuo, the residue was dissolved in MeCN and MeOH, and the product waspurified via preparative HPLC-MS (pH=2) to afford the title compound (8mg, 30%). LCMS for C₂₃H₂₈N₅O₃ (M+H)⁺: calculated m/z=422.2; found 422.1.¹H NMR (400 MHz, CD₃OD) δ 8.79 (s, 1H), 8.26 (s, 1H), 8.18 (d, J=8.0 Hz,1H), 7.84 (d, J=8.0 Hz, 1H), 4.73 (d, J=17.9 Hz, 1H), 4.66 (d, J=17.8Hz, 1H), 4.20-4.08 (m, 1H), 4.06-3.97 (m, 2H), 3.76-3.65 (m, 1H),3.61-3.51 (m, 2H), 2.00-1.88 (m, 2H), 1.88-1.70 (m, 2H), 1.41 (d, J=6.6Hz, 3H), 1.24-1.12 (m, 1H), 0.74-0.60 (m, 1H), 0.57-0.39 (m, 2H),0.39-0.26 (m, 1H).

Example 2

The compound in Table 1 was prepared by the procedures described inExample 1, using the appropriate amine in Step 4.

TABLE 1

Ex. LCMS No. Name R [M + H]⁺ NMR Spectra 2 (S)-3-Amino-6-(2-(1-cyclopropylethyl)-1- oxoisoindolin-5-yl)-N- isopropylpyrazine-2-carboxamide

380.1 ¹H NMR (400 MHz, CD₃OD) δ 8.78 (s, 1H), 8.26 (s, 1H), 8.17 (d, J =8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 4.73 (d, J = 18.1 Hz, 1H), 4.66(d, J = 17.9 Hz, 1H), 4.30- trifluoroacetate salt 4.17 (m, 1H),3.75-3.65 (m, 1H), 1.42 (d, J = 6.9 Hz, 3H), 1.32 (d, J = 6.6 Hz, 6H),1.25-1.14 (m, 1H), 0.76-0.62 (m, 1H), 0.56- 0.37 (m, 2H), 0.38-0.27 (m,1H).

Example 3.(S)-3-Amino-6-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-oxoisoindolin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamidetrifluoroacetate salt

Step 1. Methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate

To methyl 4-bromo-2-chloro-6-methylbenzoate (1.5 g, 5.7 mmol, AstatechCL9176) in CCl₄ (28 mL) was added N-bromosuccinimide (1.11 g, 6.26 mmol)and benzoyl peroxide (0.028 g, 0.11 mmol), and the reaction was heatedto reflux for 1.5 hours, and then stirred at room temperature overnight.A further portion of benzoyl peroxide (0.050 g, 0.20 mmol) was added,and the reaction was heated to reflux for 3 hours. The reaction mixturewas washed with a solution of Na₂S₂O₃ and the aqueous layer wasextracted twice with EtOAc. The combined organic extracts were driedover Na₂SO₄, filtered, and concentrated. The product was purified viaflash chromatography, eluting with a gradient from 0-50% EtOAc inhexanes, to afford the title compound (0.15 g, 67%).

Step 2. (S)-5-Bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one

To a flask containing methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate(1.91 g, 5.58 mmol) in acetonitrile (19 mL) was added(S)-1-cyclopropylethan-1-amine (0.475 g, 5.58 mmol, Aldrich 727245),followed by boric acid (0.345 g, 5.58 mmol). Potassium carbonate (1.54g, 11.2 mmol) was added portionwise over 2 minutes, and the reactionmixture was stirred overnight. The reaction mixture was filtered, andthe solids were washed with acetonitrile. The solvent was evaporatedfrom the filtrate in vacuo, and the residue was purified via flashchromatography, eluting with a gradient from 0-30% EtOAc in hexanes, toafford the title compound (1.1 g, 62%). LCMS for C₁₃H₁₄BrClNO (M+H)⁺:calculated m/z=314.0; found 314.0.

Step 3.(S)-5-Bromo-2-(1-cyclopropylethyl)-7-(methylthio)isoindolin-1-one

Sodium methanethiolate (0.30 g, 4.3 mmol) was added to(S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (0.45 g, 1.4mmol) in acetonitrile (6.0 mL) and the mixture was heated to 120° C.overnight. Upon cooling to room temperature, the reaction mixture wasfiltered through Celite®, and the Celite® was washed with EtOAc. Theorganic solution was washed with water (2×), and brine, dried overMgSO₄, filtered and concentrated to afford the title compound as ayellow solid (250 mg, 53%). LCMS for C₁₄H₁₇BrNOS (M+H)⁺: calculatedm/z=326.0; found 326.1.

Step 4.(S)-5-Bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one

To (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylthio)isoindolin-1-one(0.10 g, 0.31 mmol) in DCM (2.0 mL) at 0° C. was added m-CPBA (130 mg,0.77 mmol). After stirring for 2 hours, the reaction mixture was dilutedwith DCM and washed with saturated NaHCO₃ solution and brine. Theorganic layer was dried over MgSO₄, filtered and concentrated.Purification via flash chromatography, eluting with a gradient from0-80% EtOAc in hexanes provided the title compound as a yellow solid(0.080 g, 72%). LCMS for C₁₄H₁₇BrNO₃S (M+H)⁺: calculated m/z=358.0;found 358.1.

Step 5.(S)-2-(1-Cyclopropylethyl)-7-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

A degassed mixture of(S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one(0.10 g, 0.28 mmol), bis(pinacolato)diboron (0.11 g, 0.42 mmol),potassium acetate (0.082 g, 0.84 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.060 g, 0.017 mmol) in dioxane (3 mL) wasdegassed. The reaction mixture was heated to 80° C. for 2 hours. Uponcooling to room temperature, the reaction mixture was diluted with waterand extracted with EtOAc. The combined organic extracts were dried overNa₂SO₄, filtered and concentrated. The product was purified via flashchromatography, eluting with a gradient from 0-100% EtOAc in hexanes, toafford the title compound (0.080 g, 80%).

Step 6.3-Amino-6-bromo-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide

To 3-amino-6-bromopyrazine-2-carboxylic acid (0.030 g, 0.14 mmol,Combi-Blocks OS-2277) in DMF (1.0 mL) was added HATU (78 mg, 0.21 mmol)and Hunig's base (0.048 mL, 0.28 mmol). Tetrahydro-2H-pyran-4-amine (14mg, 0.14 mmol, J&W PharmLab 20-0092) was added, and the reaction wasstirred for 1 hour. The reaction mixture was diluted with water andextracted with EtOAc. The organic layer was dried over MgSO₄, filteredand concentrated to afford the title compound (0.040 g, 97%). LCMS forC₁₀H1₄BrN₄O₂(M+H)⁺: calculated m/z=301.0; found 301.1.

Step 7.(S)-3-Amino-6-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-oxoisoindolin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamidetrifluoroacetate salt

A microwave vial was charged with(S)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one(15 mg, 0.037 mmol, from Step 5),3-amino-6-bromo-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide (14mg, 0.044 mmol, from Step 6), Na₂CO₃ (12 mg, 0.11 mmol), dioxane (2.0mL) and water (0.5 mL). The reaction mixture was degassed with N₂, anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (3.0 mg, 3.7 μmol) was added. The mixture wasagain degassed and was heated at 100° C. for 2 hours. Upon cooling toroom temperature, the reaction mixture was diluted with EtOAc andfiltered. The filtrate was washed with water, then brine, dried overMgSO₄, filtered and concentrated. The product was purified viapreparative HPLC-MS (pH=2) to afford the title compound (4.0 mg, 17%).LCMS for C₂₄H₃₀N₅O₅S (M+H)⁺: calculated m/z=500.2; found 500.1. ¹H NMR(400 MHz, DMSO) δ 8.98 (s, 1H), 8.73 (s, 1H), 8.59 (s, 1H), 7.87 (br s,1H), 4.75 (s, 2H), 4.15-3.99 (m, 1H), 3.99-3.82 (m, 2H), 3.72-3.55 (m,4H), 3.55-3.32 (m, 2H), 1.94-1.61 (m, 4H), 1.34 (d, J=6.8 Hz, 3H),1.28-1.11 (m, 1H), 0.71-0.56 (m, 1H), 0.56-0.37 (m, 2H), 0.37-0.16 (m,1H).

Example 4

The compound of Table 2 was prepared by the procedures described inExample 3, using the appropriate amine in Step 6.

TABLE 2

Ex. LCMS No. Name R [M + H]⁺ NMR Spectra 4 (S)-3-Amino-6-(2-(1-cyclopropylethyl)-7- (methylsulfonyl)-1- oxoisoindolin-5-yl)-N-isopropylpyrazine-2-

458.1 carboxamide trifluoroacetate salt

Example 5.5-(2-(1-Cyclopropylethyl)-7-methyl-2H-indazol-5-yl)pyrazin-2-amine,trifluoroacetate

Step 1. 5-Bromo-2-(1-cyclopropylethyl)-7-methyl-2H-indazole &5-Bromo-1-(1-cyclopropylethyl)-7-methyl-1H-indazole

To a solution of 5-bromo-7-methyl-1H-indazole (50 mg, 0.24 mmol, ArkPharm) in THF (1.5 mL) was added 1-cyclopropylethan-1-ol (34 μL, 0.36mmol), triphenylphosphine (93 mg, 0.36 mmol) and DEAD (0.14 mL, 0.36mmol) sequentially, and the reaction mixture was stirred at roomtemperature for 1 h. More triphenylphosphine (93 mg, 0.36 mmol) and DEAD(0.14 mL, 0.36 mmol) were added, and the reaction mixture was stirredfor an additional 1 h. The reaction mixture was concentrated andpurified by flash chromatography (0-30% EtOAc/hexanes) to afford thetitle compounds (51 mg, 77%), which were carried forward as ˜1:1mixture. LCMS peak 1: LCMS for C13H16BrN2 (M+H)+: m/z=279.0; Found:279.0. LCMS peak 2: LCMS for C₁₃H₁₆BrN₂ (M+H)⁺: m/z=279.0; Found: 279.0.

Step 2.2-(1-Cyclopropylethyl)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole&1-(1-Cyclopropylethyl)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

5-Bromo-2-(1-cyclopropylethyl)-7-methyl-2H-indazole and5-bromo-1-(1-cyclopropylethyl)-7-methyl-1H-indazole (50 mg, 0.18 mmol,˜1:1 mixture) were combined with bis(pinacolato)diboron (68.2 mg, 0.27mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (8.8 mg, 0.01 mmol) and potassium acetate (52.7mg, 0.54 mmol) in dioxane (2 mL) and the mixture was sparged with N₂.The reaction mixture was heated to 90° C. overnight. The reactionmixture was worked up by the addition of water and extraction withEtOAc. The combined organic extracts were dried over MgSO₄, filtered,and concentrated. Flash chromatography, eluting with a gradient from0-100% EtOAc/hexanes afforded the title compounds, which were carriedforward as ˜1:1 mixture. Quantitative yield assumed. LCMS peak 1: LCMSfor C₁₉H₂₈BN₂O₂(M+H)⁺: m/z=327.2; Found: 327.2. LCMS peak 2: LCMS forC₉H₂₈BN₂O₂(M+H)⁺: m/z=327.2; Found: 327.2.

Step 3.5-(2-(1-Cyclopropylethyl)-7-methyl-2H-indazol-2H-indazol-5-yl)pyrazin-2-amine,trifluoroacetate

A mixture of 5-bromopyrazin-2-amine (17.9 mg, 0.10 mmol),2-(1-cyclopropylethyl)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole(28 mg, 86 gmol),(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (3.1 mg,4.3 μmol), and sodium carbonate (27.3 mg, 0.26 mmol) in dioxane (1 mL)and water (0.5 mL) was sparged with N₂ and heated to 100° C. for 3 h.The reaction mixture was diluted with MeOH, filtered, and purified byprep HPLC (pH 2). The first eluting peak on HPLC was determined to bethe title compound. LCMS for C₁₇H₂₀N₅(M+H)⁺: m/z=294.2; Found: 294.2. ¹HNMR (500 MHz, DMSO) δ 8.49 (d, J=1.4 Hz, 1H), 8.43 (s, 1H), 8.04 (s,1H), 8.04 (s, 1H), 7.63 (s, 1H), 3.97 (dq, J=9.3, 6.7 Hz, 1H), 2.56 (s,3H), 1.65 (d, J=6.7 Hz, 3H), 1.48-1.39 (m, 1H), 0.74-0.60 (m, 1H),0.50-0.41 (m, 2H), 0.41-0.34 (m, 1H).

Example 6.5-(2-(1-Cyclopropylethyl)-2H-benzo[d][1,2,3]triazol-5-yl)pyrazin-2-amine,trifluoroacetate

This compound was prepared by a procedure analogous to that describedfor Example 5, utilizing2-(1-cyclopropylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[d][1,2,3]triazoleinstead of2-(1-cyclopropylethyl)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazolein Step 3. The title compound eluted as the second peak on HPLC (pH 2).LCMS for C₁₅H₁₇N₆(M+H)⁺: m/z=281.1; Found: 281.1.

Example 7.(S)-5-(5-Amino-6-(1-methyl-1H-pyrazol-5-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one,trifluoroacetate salt

Step 1.(S)-5-(5-Amino-6-chloropyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one

A degassed mixture of 5-bromo-3-chloropyrazin-2-amine (0.24 g, 1.2 mmol,Ark Pharm # AK-25099),(S)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one(0.39 g, 0.96 mmol, from Example 3, Step 5), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.039 g, 0.048 mmol) in dioxane (10. mL) and aq.Na₂CO₃ solution (1.0 M, 2.9 mL, 2.9 mmol) was heated to 100° C. for 2h.Upon cooling to room temperature, the reaction mixture was diluted withaq. NH₄Cl solution and EtOAc and was stirred for 15 min, then wasfiltered through Celite®. The layers were separated, and the aqueouslayer was extracted again with EtOAc. The combined organic extracts werewashed with brine, dried over MgSO₄, filtered, and concentrated. Theproduct was purified via flash column chromatography, eluting with agradient from 0-100% EtOAc in hexanes to afford the title compound (0.10g, 26%). LCMS for C₁₈H₂₀ClN₄O₃S (M+H)⁺: calculated monoisotopicm/z=407.1; found 407.1.

Step 2.(S)-5-(5-Amino-6-(1-methyl-1H-pyrazol-5-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one,trifluoroacetate salt

A degassed mixture of(S)-5-(5-amino-6-chloropyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one(8.0 mg, 0.020 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12mg, 0.059 mmol, Aldrich #698628) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (1.6 mg, 2.0 μmol) in dioxane (0.25 mL) and aq.Na₂CO₃ (1.0 M, 0.059 mL, 0.059 mmol) was heated in a sealed vial to 120°C. for 2h. Upon cooling to room temperature, the reaction mixture wasdiluted with MeOH and MeCN, and was filtered. The product was purifiedvia preparative HPLC-MS (pH=2) to provide the title compound (3.9 mg,35%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.65 (d, J=1.5 Hz, 1H),8.56 (d, J=1.5 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 6.86-6.69 (br s, 2H),6.77 (d, J=2.0 Hz, 1H), 4.72 (s, 2H), 4.00 (s, 3H), 3.69-3.57 (m, 1H),3.63 (s, 3H), 1.33 (d, J=6.7 Hz, 3H), 1.24-1.11 (m, 1H), 0.67-0.55 (m,1H), 0.51-0.36 (m, 2H), 0.32-0.24 (m, 1H). LCMS for C₂₂H₂₅N₆O₃S (M+H)⁺:calculated m/z=453.2; found 453.1.

Examples 8-11

The compounds in Table 3 were prepared by the procedure of Example 7,using the appropriate boronic esters instead of1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inStep 2.

TABLE 3

Example Compound Name R LCMS No. ¹H NMR 8 (S)-5-(5-Amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(1- cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one, trifluoroacetate salt

Calculated for C₂₂H₂₅N₆O₃S (M + H)⁺: m/z = 453.2, found: 453.1 ¹H NMR(400 MHz, DMSO-d₆) δ 8.66 (d, J = 1.5 Hz, 1H), 8.64 (s, 1H), 8.59 (d, J= 1.5 Hz, 1H), 8.37 (s, 1H), 8.08 (d, J = 0.6 Hz, 1H), 6.59 (br s, 2H),4.72 (s, 2H), 3.95 (s, 3H), 3.73-3.55 (m, 1H), 3.64 (s, 3H), 1.33 (d, J= 6.8 Hz, 3H), 1.27-1.10 (m, 1H), 0.68-0.55 (m, 1H), 0.51-0.37 (m, 2H),0.37- 0.19 (m, 1H). 9 (S)-5-(5-Amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-2-(1- cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one, trifluoroacetate salt

Calculated for C₂₂H₂₄N₅O₃S₂ (M + H)⁺: m/z = 470.1, found: 470.1 ¹H NMR(400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.66 (d, J = 1.5 Hz, 1H), 8.54 (d, J= 1.5 Hz, 1H), 8.31 (s, 1H), 6.97 (br s, 2H), 4.73 (s, 2H), 3.69-3.60(m, 1H), 3.64 (s, 3H), 2.73 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.25-1.13(m, 1H), 0.65-0.56 (m, 1H), 0.50-0.38 (m, 2H), 0.34-0.24 (m, 1H). 10(S)-5-(5-Amino-6-(3-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7- (methylsulfonyl)isoindolin-1-one, trifluoroacetatesalt

Calculated for C₂₂H₂₅N₆O₃S (M + H)⁺: m/z = 453.2, found: 453.1 ¹H NMR(400 MHz, DMSO-d₆) δ 8.71 (d, J = 1.5 Hz, 1H), 8.63 (s, 1H), 8.52 (d, J= 1.5 Hz, 1H), 8.02 (s, 1H), 6.53 (br s, 2H), 4.71 (s, 2H), 3.68-3.58(m, 1H), 3.62 (s, 3H), 2.47 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.24-1.11(m, 1H), 0.66-0.55 (m, 1H), 0.52-0.35 (m, 2H), 0.34-0.21 (m, 1H). 11(S)-5-(5-Amino-6-(1H-pyrazol-4- yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7- (methylsulfonyl)isoindolin-1-one, trifluoroacetatesalt

Calculated for C₂₁H₂₃N₆O₃S (M + H)⁺: m/z = 439.2, found: 439.1 ¹H NMR(400 MHz, DMSO-d₆) δ 8.68 (d, J = 1.5 Hz, 1H), 8.64 (s, 1H), 8.60 (d, J= 1.5 Hz, 1H), 8.28 (s, 2H), 6.60 (br s, 2H), 4.72 (s, 2H), 3.71-3.55(m, 1H), 3.64 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.24-1.12 (m, 1H),0.70-0.54 (m, 1H), 0.53-0.34 (m, 2H), 0.34-0.20 (m, 1H).

Example 12.(S)-5-(5-Amino-6-(1H-1,2,4-triazol-1-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one,trifluoroacetate salt

Step 1. 5-Bromo-3-(1H-1,2,4-triazol-1-yl)pyrazin-2-amine

To a solution of 5-bromo-3-chloropyrazin-2-amine (0.30 g, 1.4 mmol, ArkPharm # AK-25099) and 1,2,4-triazole (0.15 g, 2.2 mmol, Aldrich #T16408) in DMF (8.0 mL) was added Cs₂CO₃ (0.70 g, 2.2 mmol) and thereaction mixture was heated to 70° C. for 1h, then overnight at 60° C.Upon cooling, the reaction mixture was partitioned between water andEtOAc, and the layers were separated. The aqueous layer was extractedonce more with EtOAc and the combined organic extracts were washed twicewith brine, dried over Na₂SO₄, filtered, and concentrated to afford thetitle compound, which was used without further purification (theoreticalyield assumed). LCMS for C₆H₆BrN₆ (M+H)⁺: calculated monoisotopicm/z=241.0; found 241.0.

Step 2.(S)-5-(5-Amino-6-(1H-1,2,4-triazol-1-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one,trifluoroacetate salt

A degassed mixture of 5-bromo-3-(1H-1,2,4-triazol-1-yl)pyrazin-2-amine(14 mg, 0.059 mmol), and(S)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one(12 mg, 0.030 mmol, from Example 3, Step 5), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (2.4 mg, 3.0 μmol) in dioxane (0.30 mL) and aq.Na₂CO₃ (1.0 M, 0.089 mL, 0.089 mmol) was heated to 100° C. for 1h. Thereaction mixture was cooled to room temperature, diluted with MeCN andMeOH, then was filtered and purified via preparative HPLC-MS (pH=2) toprovide the title compound (4.6 mg, 28%). ¹H NMR (400 MHz, DMSO-d₆) δ9.48 (s, 1H), 8.93 (s, 1H), 8.70 (d, J=1.6 Hz, 1H), 8.60 (d, J=1.5 Hz,1H), 8.45 (s, 1H), 7.56 (br s, 2H), 4.73 (s, 2H), 3.69-3.60 (m, 1H),3.64 (s, 3H), 1.34 (d, J=6.8 Hz, 3H), 1.29-1.12 (m, 1H), 0.67-0.56 (m,1H), 0.56-0.37 (m, 2H), 0.37-0.18 (m, 1H). LCMS for C₂₀H₂₂N₇O₃S (M+H)⁺:calculated m/z=440.1; found 440.1.

Example 13.(S)-5-(5-Amino-6-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)azetidin-3-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)isoindolin-1-one,0.7×trifluoroacetate salt

Step 1. tert-Butyl3-(3-amino-6-chloropyrazin-2-yl)azetidine-1-carboxylate

Zinc dust (activated by the procedure found in WO2011/143365) (0.627 g,9.59 mmol) was charged to a dry flask and suspended in DMA (2.5 ml).1,2-Dibromoethane (0.031 ml, 0.36 mmol) and TMSC1 (0.092 ml, 0.72 mmol)were added and the reaction was stirred for 25 min. tert-Butyl3-iodoazetidine-1-carboxylate (2.04 g, 7.20 mmol) (Oakwood) in DMA (6.0ml) was added slowly to the mixture which was immersed in a water bathto keep the temperature below 65° C. The mixture was stirred for 1 hourand was degassed by bubbling a stream of nitrogen subsurface for 5minutes.

A separate flask was charged with 3-bromo-5-chloropyrazin-2-amine (0.50g, 2.4 mmol, D-L Chiral Chemicals),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.118 g, 0.144 mmol) and copper(I) iodide (0.057g, 0.30 mmol). DMA (6.0 ml) was added, and the mixture was degassed bybubbling a stream of nitrogen subsurface for 5 minutes. The solutioncontaining the organozinc in DMA generated above was added, excludingany remaining zinc solids. The reaction was then heated to 80° C. for 30min. Upon cooling to room temperature, the reaction mixture waspartitioned between water and EtOAc. The aqueous layer was extractedwith two additional portions of EtOAc. The combined organic extractswere washed with water and brine, dried over sodium sulfate, filteredand concentrated. The product was purified by flash chromatography,eluting with a gradient from 0-100% EtOAc in hexanes to afford product(0.62 g, 90%). LCMS calculated for C₁₂H₁₈ClN₄O₂(M+H)⁺: monoisotopicm/z=285.1, found: 285.1. ¹H NMR (400 MHz, CDCl₃) δ 7.96-7.90 (s, 1H),4.78-4.65 (s, 2H), 4.35-4.22 (m, 4H), 3.79-3.69 (p, J=7.4 Hz, 1H),1.48-1.44 (s, 9H).

Step 2. 3-(Azetidin-3-yl)-5-chloropyrazin-2-amine hydrochloric acid salt

tert-Butyl 3-(3-amino-6-chloropyrazin-2-yl)azetidine-1-carboxylate (0.15g, 0.53 mmol, from Step 1) was treated with HCl (1.25 M in MeOH preparedby diluting c.HCl with MeOH, 7.6 mL, 9.5 mmol) and the mixture wasstirred overnight. Volatiles were removed in vacuo to afford the titlecompound (140 mg) which was used without further purification. LCMScalculated for C₇H₁₀ClN₄ (M+H)⁺: monoisotopic m/z=185.1, found: 185.0.

Step 3. (3-(3-Amino-6-chloropyrazin-2-yl)azetidin-1-yl)(1-(trifluoromethyl)cyclopropyl)methanone

To 3-(azetidin-3-yl)-5-chloropyrazin-2-amine hydrochloric acid salt(0.034 g, 0.15 mmol, from Step 2) and1-(trifluoromethyl)cyclopropane-1-carboxylic acid (0.024 g, 0.15 mmol,Astatech #66994) in DMF (1.0 mL) was added HATU (0.058 g, 0.15 mmol) andDIPEA (0.081 mL, 0.46 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with water andextracted with EtOAc (3×). The combined organic extracts were dried overNa₂SO₄, filtered and concentrated. The product was purified via flashcolumn chromatography, eluting with a gradient from 0-100% EtOAc inhexanes, to afford the title compound (23 mg, 47%). LCMS calculated forC₁₂H₁₃ClF₃N₄O (M+H)⁺: monoisotopic m/z=321.1, found: 321.1.

Step 4.(S)-5-(5-Amino-6-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)azetidin-3-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)isoindolin-1-one,0.7×trifluoroacetate salt

A degassed mixture of(3-(3-amino-6-chloropyrazin-2-yl)azetidin-1-yl)(1-(trifluoromethyl)cyclopropyl)methanone(0.023 g, 0.072 mmol, from Step 3),(S)-2-(1-cyclopropylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one(0.023 g, 0.072 mmol, from Example 1, Step 2) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (2.9 mg, 3.6 μmol) in dioxane (1.4 mL) and aq.Na₂CO₃ (1.0 M, 0.22 mL, 0.22 mmol) was heated to 120° C. for 6 hours ina sealed vial. The reaction mixture was cooled to room temperature,diluted with MeOH, filtered and purified via preparative HPLC-MS (pH=2),to provide a mixture of the desired product and unreacted(3-(3-amino-6-chloropyrazin-2-yl)azetidin-1-yl)(1-(trifluoromethyl)cyclopropyl)methanone.The mixture so obtained was combined with(S)-2-(1-cyclopropylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one(0.023 g, 0.072 mmol, from Example 1, Step 2) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (2.9 mg, 3.6 μmol) in dioxane (1.4 mL) and aq.Na₂CO₃ (1.0 M, 0.22 mL, 0.22 mmol) and was heated to 120° C. for 1.5hours in a sealed vial. Upon cooling to room temperature, the reactionmixture was diluted with MeOH, filtered and purified via preparativeHPLC-MS (pH=2) to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ 8.61 (s, 1H), 8.22 (s, 1H), 8.12 (dd, J⁼8.1, 1.4 Hz, 1H), 7.71 (d,J=8.0 Hz, 1H), 6.58 (br s, 2H), 4.81-4.64 (br m, 1H), 4.60 (s, 2H),4.46-4.22 (br m, 3H), 4.10-3.98 (m, 1H), 3.67-3.58 (m, 1H), 1.31 (d,J=6.8 Hz, 3H), 1.25-1.19 (br m, 4H), 1.19-1.08 (m, 1H), 0.64-0.53 (m,1H), 0.47-0.35 (m, 2H), 0.30-0.19 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−65.68 (s), −74.43 (s). LCMS calculated for C₂₅H2₇F3NsO₂ (M+H)⁺:m/z=486.2, found: 486.2.

Example A. THP-1 RPS6 ELISA Assay

To measure the Phosphorylated Ribosomal Protein S6 (RPS6) in celllysates, THP-1 cells (Human Acute Monocytic Leukemia) are purchased fromATCC (Manassas, Va.) and maintained in RPMI with 10% FBS (Gibco/LifeTechnologies, Carlsbad, Calif.). For the assay, THP-1 cells are serumstarved overnight in RPMI, then plated in RPMI (2×10⁵ cells/well in 90μL) into 96-well flat-bottom tissue culture treated plates (Corning,Corning, N.Y.), in the presence or absence of a concentration range oftest compounds. Covered plates are incubated for 2 hours at 37° C., 5%CO₂ then treated with or without 10 nM MCP-1 (MYBioSource, San Diego,Calif.) for 15 minutes at 37° C., 5% CO₂. Plates are centrifuged at 1600RPM and supernatants are removed. Cells are lysed in Lysis Buffer (CellSignaling, Danvers, Mass.) with Protease Inhibitor (Calbiochem/EMD,Germany), PMSF (Sigma, St Louis Mo.), HALTS (Thermo Fisher, Rockford,Ill.) for 30 min on wet ice. Cell lysates are frozen at −80 OC beforetesting. The lysates are tested in the Human/Mouse/Rat Phospho-RPS6ELISA (R&D Systems, Inc. Minn, Minn.). The plate is measured using amicroplate reader (SpectraMax M5—Molecular Devices, LLC Sunnyvale,Calif.) set to 450 nm with a wavelength correction of 540. IC₅₀determination is performed by fitting the curve of inhibitor percentinhibition versus the log of the inhibitor concentration using theGraphPad Prism 5.0 software.

Example B. PI3K-γ Scintillation Proximity Assay

Materials:

[γ-³³P]ATP (10 mCi/mL) and Wheat Germ Agglutinin (WGA) YSi SPAScintillation Beads was purchased from Perkin Elmer (Waltham, Mass.).Lipid kinase substrate, D-myo-Phosphatidylinositol 4,5-bisphosphate(PtdIns(4,5)P2)D (+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked(PIP2), CAS 204858-53-7, was purchased from Echelon Biosciences (SaltLake City, Utah). PI3Kγ (p110γ) Recombinant Human Protein was purchasedfrom Life technology (Grand Island, N.Y.). ATP, MgCl₂, DTT, EDTA, MOPSand CHAPS were purchased from Sigma Aldrich (St. Louis, Mo.).

The kinase reaction was conducted in polystyrene 384-well GreinerBio-one white plate from Thermo Fisher Scientific in a final volume of25 μL. Inhibitors were first diluted serially in DMSO and added to theplate wells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 2%. The PI3Kγ assay was carriedout at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl₂, 5 mM DTT andCHAPS 0.03%. Reactions were initiated by the addition of ATP, the finalreaction mixture consisted of 20 μM PIP2, 2 μM ATP, 0.5 μCi [γ-³³P] ATP,13 nM PI3Kγ. Reactions were incubated for 120 min and terminated by theaddition of 40 μL SPA beads suspended in quench buffer: 163 mM potassiumphosphate pH 7.8, 20% glycerol, 25 mM EDTA. The final concentration ofSPA beads is 1.0 mg/mL. After the plate sealing, plates were shakenovernight at room temperature and centrifuged at 1500 rpm for 10 min,the radioactivity of the product was determined by scintillationcounting on Topcount (Perkin-Elmer). IC₅₀ determination was performed byfitting the curve of percent of the solvent control activity versus thelog of the inhibitor concentration using the GraphPad Prism 6.0software.

Example C. PI3Kδ Scintillation Proximity Assay

Materials: [γ-³³P]ATP (10 mCi/mL) and Wheat Germ Agglutinin (WGA) YSiSPA Scintillation Beads was purchased from Perkin Elmer (Waltham,Mass.). Lipid kinase substrate, D-myo-Phosphatidylinositol4,5-bisphosphate (PtdIns(4,5)P2)D (+)-sn-1,2-di-O-octanoylglyceryl,3-O-phospho linked (PIP2), CAS 204858-53-7, was purchased from EchelonBiosciences (Salt Lake City, Utah). PI3Kδ (p110δ/p85α) Recombinant HumanProtein was purchased from Eurofins (St Charles, Mo.). ATP, MgCl₂, DTT,EDTA, MOPS and CHAPS were purchased from Sigma Aldrich (St. Louis, Mo.).

The kinase reaction was conducted in polystyrene 384-well GreinerBio-one white plate from Thermo Fisher Scientific in a final volume of25 μL. Inhibitors were first diluted serially in DMSO and added to theplate wells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 2%. The PI3K6 assay was carriedout at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl₂, 5 mM DTT andCHAPS 0.03%. Reactions were initiated by the addition of ATP, the finalreaction mixture consisted of 20 μM PIP2, 2 μM ATP, 0.5 μCi [γ-³³P] ATP,3.4 nM PI3K6. Reactions were incubated for 120 min and terminated by theaddition of 40 μL SPA beads suspended in quench buffer: 163 mM potassiumphosphate pH 7.8, 20% glycerol, 25 mM EDTA. The final concentration ofSPA beads is 1.0 mg/mL. After the plate sealing, plates were shakenovernight at room temperature and centrifuged at 1500 rpm for 10 min,the radioactivity of the product was determined by scintillationcounting on Topcount (PerkinElmer). IC₅₀ determination was performed byfitting the curve of percent of the solvent control activity versus thelog of the inhibitor concentration using the GraphPad Prism 6.0software.

The compounds of the Examples were tested in the assays described inExamples A, B and C and found to have the ICsos are shown in Table A.

TABLE A PI3Kγ PI3Kδ PI3Kγ_THP1_RPS6_ELISA Ex. No. IC₅₀ (nM) IC₅₀ (nM)IC₅₀ (nM) 1 + +++ #### 2 + +++ #### 3 + ++ ## 4 + +++ #### 5 ++ ++++ NA6 +++ ++++ NA 7 + +++ #### 8 + +++ ### 9 + ++ ### 10 + +++ #### 11 + +++NA 12 + +++ #### 13 + ++++ NA + refers to IC₅₀ of ≤100 nM; ++ refers toIC₅₀ of ≤500 nM; +++ refers to an IC₅₀ of <2000 nM; ++++ refers to anIC₅₀ of ≥2000 nM. # refers to IC₅₀ of ≤100 nM; ## refers to IC₅₀ of ≤500nM; ### refers to IC₅₀ of <1000 nM; #### refers to an IC₅₀ of ≥1000 nM.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula (IIu):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a1), SR^(a1), NHOR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)NR^(c1)(OR^(a1)), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), and NR^(c1)C(O)NR^(c1)R^(d1),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R¹ are each optionally substituted with 1, 2, 3, 4, 5, 6, 7,or 8 independently selected R^(1A) substituents; each R^(a1), R^(b1),and R^(c1) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a1),R^(b1), and R^(c1) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(1A) substituents; each R^(d1) isindependently selected from C₂₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₂₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₂₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆-C₁₀ aryl-C₂₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(d1) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(1A) substituents; or, any R^(c1) and R^(d1), attached to thesame N atom, together with the N atom to which they are attached, form a5-10 membered heteroaryl group or a 4-10 membered heterocycloalkylgroup, wherein the 5-10 membered heteroaryl group or 4-10 memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6,7, or 8 independently selected R^(1A) substituents; each R^(1A) isselected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a1), SR^(a11), NHOR^(a11),C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)NR^(c11)(OR^(a11)), C(O)OR^(a11),OC(O)R^(b11), OC(O)NR^(c11)R^(d11), NR^(c11)R^(d11),NR^(c1)NR^(c1)R^(d11), NR¹¹C(O)R^(b11), NR^(c11)C(O)OR^(a11),NR^(c11)C(O)NR^(c11)R^(d11), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(1A) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(M)substituents; each R^(a1), R^(b11), R^(c11), and R^(d11) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a11), R^(b1),R^(c11) and R^(d11) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(M) substituents; or, any R^(c11)and R^(d11), attached to the same N atom, together with the N atom towhich they are attached, form a 5-10 membered heteroaryl group or a 4-10membered heterocycloalkyl group, wherein the 5-10 membered heteroarylgroup or 4-10 membered heterocycloalkyl group is optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(M)substituents; each R^(M) is independently selected from D, OH, NO₂, CN,halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₆ cycloalkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino,thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl,C₁₋₃ alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl,C₁₋₄ alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino,C₁₋₃ alkylcarbonyloxy, aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy,di(C₁₋₃ alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl,C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino; R⁶ isselected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a6), SR^(a6), NHOR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)NR⁶(OR^(a6)), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6),C(═NR^(e6))R^(b6), C(═NOH)R^(b6), C(═NCN)R^(b6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),NR⁶C(═NOH)NR^(c6)R^(d6), NR⁶C(═NCN)NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))R^(b6), NR^(c6)S(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)(═NR^(e6))R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),S(O)₂NR^(c6)R^(d6), S(O)(═NR^(e6))R^(b6), OS(O)(═NR^(e6))R^(b6),OS(O)₂R^(b6), and SF₅, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁶ are each optionally substituted with1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(6A) substituents;each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a6), R^(b6), R^(c6)and R^(d6) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or8 independently selected R^(6A) substituents; or, any R^(c6) and R^(d6),attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl group or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl group or4-10 membered heterocycloalkyl group is optionally substituted with 1,2, 3, 4, 5, 6, 7, or 8 independently selected R^(6A) substituents; eachR^(e6) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;each R^(6A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a61),SR^(a61), NHOR^(a61), C(O)R^(b61), C(O)NR^(c61)R^(d61),C(O)NR^(c61)(OR^(a61)), C(O)OR^(a61), OC(O)R^(b61),OC(O)NR^(c61)R^(d61), NR^(c61)R^(d61), NR^(c61)NR^(c61)R^(d61),NR^(c61)C(O)R^(b61), NR^(c61)C(O)OR^(a61), NR^(c61)C(O)NR^(c61)R^(d61),C(═NR^(e61))R^(b61), C(═NOH)R^(b61), C(═NCN)R^(b61),C(═NR^(e61))NR^(c61)R^(d61), NR^(c61)C(═NR^(e61))NR^(c61)R^(d61),NR^(c61)C(═NOH)NR^(c61)R^(d61), NR^(c61)C(═NCN)NR^(c61)R^(d61),NR^(c61)C(═NR^(e61))R^(b61), NR^(c61)S(O)NR^(c61)R^(d61),NR^(c61)S(O)R^(b61), NR^(c61)S(O)₂R^(b61),NR^(c61)S(O)(═NR^(e61))R^(b61), NR^(c61)S(O)₂NR^(c61)R^(d61),S(O)R^(b61), S(O)NR^(c61)R^(d61), S(O)₂R^(b61), S(O)₂NR^(c61)R^(d61),S(O)(═NR^(e61))R^(b61), OS(O)(═NR^(e61))R^(b61), OS(O)₂R^(b61) and SF₅,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R^(6A) are each optionally substituted with 1, 2, 3, 4, 5, 6,7, or 8 independently selected R^(M) substituents; each R^(a61),R^(b61), R^(c61), and R^(d61) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a61), R^(b61), R^(c61) and R^(d61)are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(M) substituents; or, any R^(c61) and R^(d61),attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl group or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl group or4-10 membered heterocycloalkyl group is optionally substituted with 1,2, 3, 4, 5, 6, 7, or 8 independently selected R^(M) substituents; eachR^(e61) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;X⁹ is NR⁹N or C(R⁹)₂; X¹¹ is NR^(11N) or C(R¹¹)₂; R^(9N) is selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b9N), C(O)NR^(9N)R^(d9N),C(O)OR^(a9N), C(═NR^(e9N))R^(b9N)C(═NR^(e9)N)NR^(c9)NR^(d9)N,C(═NCN)NR⁹NR^(d9)N, C(═NOR^(a9)N)NR^(c9N), S(O)₂R^(b9N),S(O)(═NR⁹N)R^(d9)N and S(O)₂NR^(9N)R^(d9N), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(9N) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(9NA) substituents; each R^(a9N), R^(b9N), R^(c9N), andR^(d9N) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a9N),R^(b9N), R^(c9N), and R^(d9N) are each optionally substituted with 1, 2,3, 4, 5, 6, 7, or 8 independently selected R^(9NA) substituents; or, anyR^(c9N) and R^(d9N), attached to the same N atom, together with the Natom to which they are attached, form a 5-10 membered heteroaryl groupor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl group or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selectedR^(9NA) substituents; each R^(e9N) is independently selected from H, OH,CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, and C₂₋₆ alkynyl; each R^(9NA) is selected from H, D, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a9N2), SR^(a9N2), NHOR^(a9N2), C(O)R^(b9N2),C(O)NR^(9N2)R^(d9N2), C(O)NR^(c9N2)(OR^(a9N2)), C(O)OR^(a9N2),OC(O)R^(b9N2), OC(O)NR^(c9N2)R^(d9N2), NR^(c9N2)R^(d9N2),NR^(c9N2)NR^(c9N2)R^(d9N2), NR^(c9N2)C(O)R^(b9N2),NR^(c9N2)C(O)OR^(a9N2), and NR^(9N2)C(O)NR^(c9N2)R^(d9N2), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(9NA) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents; each R^(a9N2), R^(b9N2), R^(c9N2), and R^(d9N2) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a9N2), R^(b9N2), R^(c9N2) andR^(d9N2) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents; or, any R^(c9N2) andR^(d9N2), attached to the same N atom, together with the N atom to whichthey are attached, form a 5-6 membered heteroaryl group or a 4-7membered heterocycloalkyl group, wherein the 5-6 membered heteroarylgroup or 4-7 membered heterocycloalkyl group is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; each R⁹ isindependently selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a91),SR^(a91), NHOR^(a91), C(O)R^(b91), C(O)NR^(c91)R^(d91),C(O)NR^(c91)(OR^(a9)), C(O)OR^(a91), OC(O)R^(b91), OC(O)NR^(c91)R^(d91),NR^(c91)R^(d91), NR^(c91)NR^(c91)R^(d91), NR^(c91)C(O)R^(b91),NR^(c91)C(O)OR^(a91), and NR^(c91)C(O)NR^(c91)R^(d91), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁹ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(9A) substituents; or, alternatively, two R⁹ groups togetherform an oxo group; each R^(a91), R^(b91), R^(c91), and R^(d91) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a91), R^(b91),R^(c91) and R^(d91) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(9A) substituents; or, any R^(c91)and R^(d91), attached to the same N atom, together with the N atom towhich they are attached, form a 5-10 membered heteroaryl group or a 4-10membered heterocycloalkyl group, wherein the 5-10 membered heteroarylgroup or 4-10 membered heterocycloalkyl group is optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(9A)substituents; each R^(9A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a92), SR^(a92),NHOR^(a92), C(O)R^(b92), C(O)NR^(c92)R^(d92), C(O)NR^(c92)(OR^(a92)),C(O)OR^(a92), OC(O)R^(b92), OC(O)NR^(c92)R^(d92), NR^(c92)R^(d92),NR^(c92)NR^(c92)R^(d92), NR^(c92)C(O)R^(b92), NR^(c92)C(O)OR^(a92), andNR^(c92)C(O)NR^(c92)R^(d92), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(9A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; eachR^(a92), R^(b92), R^(c92), and R^(d92) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a92), R^(b92), R^(c92) and R^(d92) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; or, anyR^(c92) and R^(d92), attached to the same N atom, together with the Natom to which they are attached, form a 5-6 membered heteroaryl group ora 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl group or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents; R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b1)N,C(O)NR^(c10N)R^(d10N), C(O)OR^(a10N), C(═NR^(e10N))R^(b10N)C(═NR^(e10N))NR^(c10N)R^(d10N), C(═NCN)NR^(c10N)R^(d10N),C(═NOR^(a10N))NR^(c10N), S(O)₂R^(b10N), S(O)(═NR^(c10N))R^(d10N), andS(O)₂NR^(c10N)R^(d10N), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(10NA)substituents; each R^(a10N), R^(b10N), R^(c10N), and R^(d10N) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a10N), R^(b10N),R^(c10N), and R^(d10N) are each optionally substituted with 1, 2, 3, 4,5, 6, 7, or 8 independently selected R^(10NA) substituents; or, anyR^(c10N) and R^(d10N), attached to the same N atom, together with the Natom to which they are attached, form a 5-10 membered heteroaryl groupor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl group or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selectedR^(10NA) substituents; each R^(e10N) is independently selected from H,OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, and C₂₋₆ alkynyl; each R^(10NA) is selected from H, D, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a10N2), SR^(a10N2), NHOR^(a10N2), C(O)R^(b10N2),C(O)NR^(c10N2)R^(d10N2), C(O)NR^(c10N2)(OR^(a10N2)), C(O)OR^(a10N2),OC(O)R^(b10N2), OC(O)NR^(c10N2)R^(d10N2), NR^(c10N2)R^(d10N2),NR^(c10N2)NR^(c10N2)R^(d10N2), NR^(c10N2)C(O)R^(b10N2),NR^(c10N2)C(O)OR^(a10N2), and NR^(c10N2)C(O)NR^(c10N2)R^(d10N2), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10NA) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents; each R^(a10N2), R^(b10N2), R^(c10N2), and R^(d10N2) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a10N2), R^(b10N2), R^(c10N2) andR^(d10N2) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents; or, any R^(c10N2) andR^(d10N2), attached to the same N atom, together with the N atom towhich they are attached, form a 5-6 membered heteroaryl group or a 4-7membered heterocycloalkyl group, wherein the 5-6 membered heteroarylgroup or 4-7 membered heterocycloalkyl group is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; R^(11N) isselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₆-C₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b11)N, C(O)NR^(c11)NR^(d11)N,C(O)OR^(a11N), C(═NR^(e11N))R^(b11)N C(═NR^(e11N))NR^(c11N)R^(d11)N,C(═NCN)NR^(c11N)R^(d1)N, C(═NOR^(a11N))NR^(c11)N,S(O)₂R^(b11N)S(O)(═NR^(c11N))R^(d1)N, and S(O)₂NR^(c11N)R^(d11N),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(11N) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or8 independently selected R^(11NA) substituents; each R^(a11N), R^(b11)N,R^(c11)N, and R^(d11N) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a11N), R^(b11)N, R^(c11N), andR^(d11N) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(11NA) substituents; or, any R^(c11N) andR^(d11)N, attached to the same N atom, together with the N atom to whichthey are attached, form a 5-10 membered heteroaryl group or a 4-10membered heterocycloalkyl group, wherein the 5-10 membered heteroarylgroup or 4-10 membered heterocycloalkyl group is optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(11NA)substituents; each R^(e11N) is independently selected from H, OH, CN,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; each R^(11NA) is independently selected from H, D,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a11N2), SR^(a11N2), NHOR^(a11N2), C(O)R^(b11N2),C(O)NR^(c11N2)R^(d11N2), C(O)NR^(c11N2)(OR^(a11N2)), C(O)OR^(a11N2),OC(O)R^(b11N2) OC(O)NR^(c11N2)R^(d11N2), NR^(c11N2)R^(d11N2),NR^(c11N2)NR^(c11N2)R^(d11N2), NR^(c11N2)C(O)R^(b11N2),NR^(c11N2)C(O)OR^(a11N2), and NR^(c11N2)C(O)NR^(c11N2)R^(d11N2), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(11NA) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents; each R^(a11N2), R^(b11N2), R^(c11N2), and R^(d11N2) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a11N2), R^(b11N2), R^(c11N2) andR^(d11N2) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents; or, any R^(c11N2) andR^(d11N2), attached to the same N atom, together with the N atom towhich they are attached, form a 5-6 membered heteroaryl group or a 4-7membered heterocycloalkyl group, wherein the 5-6 membered heteroarylgroup or 4-7 membered heterocycloalkyl group is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; each R¹¹is independently selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a11),SR^(a111), NHOR^(a11), C(O)R^(b111), C(O)NR^(c11)R^(d111),C(O)NR^(c111)(OR^(a11)), C(O)OR^(a111), OC(O)R^(b111),OC(O)NR^(c11)R^(d111), NR^(c11)R^(d1), NR^(c111)NR^(c11)R^(d111)NR^(c111)C(O)R^(b111), NR^(c111)C(O)OR^(a111), andNR^(c111)C(O)NR^(c11)R^(d11) wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R¹¹ are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(11A)substituents; each R^(a111), R^(b111), R^(c111), and R^(d111) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a111), R^(b111),R^(c11) and R^(d11) are each optionally substituted with 1, 2, 3, 4, 5,6, 7, or 8 independently selected R^(11A) substituents; or, any R^(c111)and R^(d111), attached to the same N atom, together with the N atom towhich they are attached, form a 5-10 membered heteroaryl group or a 4-10membered heterocycloalkyl group, wherein the 5-10 membered heteroarylgroup or 4-10 membered heterocycloalkyl group is optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(11A)substituents; and each R^(11A) is selected from H, D, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a112), SR^(a112),NHOR^(a112), C(O)R^(b112), C(O)NR^(c112)R^(d112),C(O)NR^(c112)(OR^(a112)), C(O)OR^(a112), OC(O)R^(b112),OC(O)NR^(c112)R^(d112), NR^(c112)R^(d112), NR^(c112)NR^(c112)R^(d112),NR^(c112)C(O)R^(b112), NR^(c112)C(O)OR^(a112), andNR^(c112)C(O)NR^(c112)R^(d112), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(11A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; and eachR^(a112), R^(b112), R^(c112), and R^(d112) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a112), R^(b112), R^(c112) and R^(d112) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents; or, any R^(c112) and R^(d112), attached to the same Natom, together with the N atom to which they are attached, form a 5-6membered heteroaryl group or a 4-7 membered heterocycloalkyl group,wherein the 5-6 membered heteroaryl group or 4-7 memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents.
 2. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R¹ is selectedfrom H, D, C₁₋₆ alkyl, C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)NR^(c1)(OR^(a1)), C(O)OR^(a1), OC(O)R^(b1)OC(O)NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein the 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are optionallysubstituted with 1 or 2 independently selected R^(1A) substituents. 3.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from H, C(O)R^(b1), C(O)NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein the 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are optionallysubstituted with 1 or 2 independently selected R^(1A) substituents. 4.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from H, C(O)NR^(c1)R^(d1), 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl, wherein the 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are optionally substitutedwith 1 or 2 independently selected R^(1A) substituents.
 5. The compoundof any one of claims 1 to 4, or a pharmaceutically acceptable saltthereof, wherein: each R^(a1), R^(b1), and R^(c1) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6 memberedheterocycloalkyl of R^(a1), R^(b1), R^(c1) and R^(d1) are eachoptionally substituted with 1 or 2 independently selected R^(1A)substituents; and each R^(d1) is independently selected from C₂₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, and 4-6 membered heterocycloalkyl, wherein the C₂₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-6 membered heterocycloalkyl of R^(d1) is optionallysubstituted with 1 or 2 independently selected R^(1A) substituents. 6.The compound of any one of claims 1 to 4, or a pharmaceuticallyacceptable salt thereof, wherein: each R^(c1) is independently selectedfrom H, C₁₋₆ alkyl, and 4-6 membered heterocycloalkyl, wherein the C₁₋₆alkyl and 4-6 membered heterocycloalkyl of R^(c1) is optionallysubstituted with 1 or 2 independently selected R^(1A) substituents; andeach R^(d1) is independently selected from C₂₋₆ alkyl, and 4-6 memberedheterocycloalkyl, wherein the C₂₋₆ alkyl and 4-6 memberedheterocycloalkyl of R^(d1) is optionally substituted with 1 or 2independently selected R^(1A) substituents.
 7. The compound of any oneof claims 1 to 4, or a pharmaceutically acceptable salt thereof, whereineach R^(c1) is H and each R^(d1) is independently selected from C₂₋₆alkyl and 4-6 membered heterocycloalkyl.
 8. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein R¹ is selected fromH, tetrahydropyranylaminocarbonyl, isopropylaminocarbonyl,1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl,2-methylthiazol-5-yl, 3-methyl-1H-pyrazol-4-yl, 1H-pyrazol-4-yl,1H-1,2,4-triazol-1-yl, and1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)azetidin-3-yl.
 9. Thecompound of any one of claims 1 to 8, or a pharmaceutically acceptablesalt thereof, wherein R⁶ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6).
 10. The compound of any one ofclaims 1 to 9, or a pharmaceutically acceptable salt thereof, whereineach R^(b6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.
 11. The compoundof any one of claims 1 to 8, or a pharmaceutically acceptable saltthereof, wherein R⁶ is selected from H, halo, C₁₋₆ alkyl, S(O)R^(b6),and S(O)₂R^(b6), and R^(b6) is selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.
 12. The compound of any oneof claims 1 to 8, or a pharmaceutically acceptable salt thereof, whereinR⁶ is selected from H, methyl, and S(O)₂CH₃.
 13. The compound of any oneof claims 1 to 12, or a pharmaceutically acceptable salt thereof,wherein X⁹ is C(R⁹)₂.
 14. The compound of any one of claims 1 to 13, ora pharmaceutically acceptable salt thereof, wherein each R⁹ isindependently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, of R⁹ are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents; or, alternatively, two R⁹groups together form an oxo group.
 15. The compound of any one of claims1 to 13, or a pharmaceutically acceptable salt thereof, wherein each R⁹is H.
 16. The compound of any one of claims 1 to 13, or apharmaceutically acceptable salt thereof, wherein two R⁹ groups togetherform an oxo group.
 17. The compound of any one of claims 1 to 16, or apharmaceutically acceptable salt thereof, wherein R^(10N) is selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(10NA)substituents.
 18. The compound of any one of claims 1 to 16, or apharmaceutically acceptable salt thereof, wherein R^(10N) is selectedfrom C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-6 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl- and (4-6 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(10N) are each optionally substituted with 1 or 2 independentlyselected R^(10NA) substituents.
 19. The compound of any one of claims 1to 16, or a pharmaceutically acceptable salt thereof, wherein R^(10N) isselected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆cycloalkyl-C₁₋₆ alkyl- of R^(10N) are each optionally substituted with 1or 2 independently selected R^(10NA) substituents.
 20. The compound ofany one of claims 1 to 16, or a pharmaceutically acceptable saltthereof, wherein R^(10N) is C₃₋₆ cycloalkyl-C₁₋₆ alkyl-.
 21. Thecompound of any one of claims 1 to 16, or a pharmaceutically acceptablesalt thereof, wherein R^(10N) is cyclopropylethyl.
 22. The compound ofany one of claims 1 to 21, or a pharmaceutically acceptable saltthereof, wherein X¹¹ is C(R¹¹)₂.
 23. The compound of any one of claims 1to 22, or a pharmaceutically acceptable salt thereof, wherein each R¹¹is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl with 1 or 2 independently selected R^(11A) substituents.24. The compound of any one of claims 1 to 21, or a pharmaceuticallyacceptable salt thereof, wherein X¹¹ is CH₂.
 25. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein: R¹ isselected from H, D, C₁₋₆ alkyl, C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)NR^(c1)(OR^(a1)), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein the 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are optionallysubstituted with 1 or 2 independently selected R^(1A) substituents; eachR^(a1), R^(b1), and R^(c1) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a1), R^(b1), and R^(c1) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(1A)substituents; each R^(d1) is independently selected from C₂₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₂₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₂₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₂₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(d1) is optionally substituted with1, 2, 3, or 4 independently selected R^(1A) substituents; each R^(1A) isselected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, CN, NO₂, NH₂ and C(O)R^(b11); each R^(b11) is independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₁₀ cycloalkyl, whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₁₀ cycloalkyl of R^(b11) are eachoptionally substituted with 1 or 2 independently selected R^(M)substituents; each R^(M) is independently selected from C₁₋₆ alkyl andC₁₋₆ haloalkyl; R⁶ is selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6); each R^(b6), R^(c6), and R^(d6) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; X⁹ is C(R⁹)₂; X¹¹ is C(R¹¹)₂; each R⁹ isindependently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, of R⁹ are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents; or, alternatively, two R⁹groups together form an oxo group; R^(10N) is selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(10NA) substituents; eachR^(10NA) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂; each R¹¹ isindependently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl with 1 or 2 independently selected R^(11A) substituents;and each R^(11A) is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, and NH₂.
 26. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: R¹ is selected from H, C(O)R^(b1), C(O)NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein the 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are optionallysubstituted with 1 or 2 independently selected R^(1A) substituents; eachR^(a1), R^(b1), and R^(c1) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, and 4-6 membered heterocycloalkyl, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-6 membered heterocycloalkyl of R^(a1), R^(b1) andR^(c1) are each optionally substituted with 1 or 2 independentlyselected R^(1A) substituents; each R^(d1) is independently selected fromH, C₂₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl,wherein the C₂₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkylof R^(d1) is optionally substituted with 1 or 2 independently selectedR^(1A) substituents; each R^(1A) is selected from H, D, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, NH₂ andC(O)R^(b11); each R^(b11) is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, and C₃₋₁₀ cycloalkyl, wherein the C₁₋₆ alkyl, C₁₋₆haloalkyl, and C₃₋₁₀ cycloalkyl of R^(b11) are each optionallysubstituted with 1 or 2 independently selected R^(M) substituents; eachR^(M) is independently selected from C₁₋₃ alkyl and C₁₋₃ haloalkyl; R⁶is selected from H, C₁₋₆ alkyl, S(O)R^(b6), and S(O)₂R^(b6); R^(b6) isselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl; X⁹ is C(R⁹)₂; X¹¹ is C(R¹¹)₂; each R⁹ is independently selectedfrom H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, of R⁹ are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(9A)substituents; or, alternatively, two R⁹ groups together form an oxogroup; R^(10N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(10N) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(10NA) substituents; each R^(10NA) is selected from H, D, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,NO₂, and NH₂; each R¹¹ is independently selected from H, D, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.
 27. The compound ofclaim 1, selected from:(S)-3-amino-6-(2-(1-cyclopropylethyl)-1-oxoisoindolin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide;(S)-3-amino-6-(2-(1-cyclopropylethyl)-1-oxoisoindolin-5-yl)-N-isopropylpyrazine-2-carboxamide;(S)-3-amino-6-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-oxoisoindolin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide;and(S)-3-amino-6-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-oxoisoindolin-5-yl)-N-isopropylpyrazine-2-carboxamide;or a pharmaceutically acceptable salt thereof.
 28. The compound of claim1, selected from:(S)-5-(5-Amino-6-(1-methyl-1H-pyrazol-5-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one;(S)-5-(5-Amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one;(S)-5-(5-Amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one;(S)-5-(5-Amino-6-(3-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one;(S)-5-(5-Amino-6-(1H-pyrazol-4-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one;(S)-5-(5-Amino-6-(1H-1,2,4-triazol-1-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one;and(S)-5-(5-Amino-6-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)azetidin-3-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)isoindolin-1-one;or a pharmaceutically acceptable salt thereof.
 29. A compound selectedfrom:(S)-3-amino-6-(2-(1-cyclopropylethyl)-1-oxoisoindolin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide;(S)-3-amino-6-(2-(1-cyclopropylethyl)-1-oxoisoindolin-5-yl)-N-isopropylpyrazine-2-carboxamide;(S)-3-amino-6-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-oxoisoindolin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide;and(S)-3-amino-6-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-oxoisoindolin-5-yl)-N-isopropylpyrazine-2-carboxamide;5-(2-(1-cyclopropylethyl)-7-methyl-2H-indazol-5-yl)pyrazin-2-amine;5-(2-(1-cyclopropylethyl)-2H-benzo[d][1,2,3]triazol-5-yl)pyrazin-2-amine;(S)-5-(5-Amino-6-(1-methyl-1H-pyrazol-5-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one;(S)-5-(5-Amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one;(S)-5-(5-Amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one;(S)-5-(5-Amino-6-(3-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one;(S)-5-(5-Amino-6-(1H-pyrazol-4-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one;(S)-5-(5-Amino-6-(1H-1,2,4-triazol-1-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one;and(S)-5-(5-Amino-6-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)azetidin-3-yl)pyrazin-2-yl)-2-(1-cyclopropylethyl)isoindolin-1-one;or a pharmaceutically acceptable salt thereof.
 30. A pharmaceuticalcomposition comprising a compound of any one of claims 1 to 29, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient or carrier.
 31. A method of inhibiting an activityof PI3Kγ kinase, comprising contacting the kinase with a compound of anyone of claims 1 to 29, or a pharmaceutically acceptable salt thereof.32. The method of claim 31, wherein said compound, or pharmaceuticallyacceptable salt thereof, is a selective inhibitor for PI3Kγ over one ormore of PI3Kα, PI3Kβ, and PI3Kδ.
 33. A method of treating a disease ordisorder in a patient, wherein said disease or disorder is associatedwith abnormal expression or activity of PI3Kγ kinase, comprisingadministering to said patient a therapeutically effective amount of acompound of any one of claims 1 to 29, or a pharmaceutically acceptablesalt thereof.
 34. The method of claim 33, wherein the disease ordisorder is an autoimmune disease or disorder, cancer, cardiovasculardisease, or neurodegenerative disease.
 35. The method of claim 33,wherein the disease or disorder is lung cancer, melanoma, pancreaticcancer, breast cancer, prostate cancer, liver cancer, color cancer,endometrial cancer, bladder cancer, skin cancer, cancer of the uterus,renal cancer, gastric cancer, seminoma, teratocarcinoma, astrocytoma,neuroblastoma, glioma, or sarcoma.
 36. The method of claim 35, whereinthe sarcoma is Askin's tumor, sarcoma botryoides, chondrosarcoma,Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma,osteosarcoma, alveolar soft part sarcoma, angiosarcoma, cystosarcomaphyllodes, dermatofibrosarcoma protuberans, desmoid tumor, desmoplasticsmall round cell tumor, epithelioid sarcoma, extraskeletalchondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma,gastrointestinal stromal tumor (GIST), hemangiopericytoma,hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma,lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheathtumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, orundifferentiated pleomorphic sarcoma.
 37. The method of claim 33,wherein the disease or disorder is acute myeloid leukemia, acutemonocytic leukemia, small lymphocyctic lymphoma, chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma,T-cell actute lymphoblasic leukemia (T-ALL), cutaneous T-cell lymphoma,large granular lymphocytic leukemia, mature (peripheral) t-cell neoplasm(PTCL), anaplastic large cell lymphoma (ALCL), or lymphoblasticlymphoma.
 38. The method of claim 37, wherein the mature (peripheral)t-cell neoplasm (PTCL) is T-cell prolymphocytic leukemia, T-cellgranular lymphocytic leukemia, aggressive NK-cell leukemia, mycosisfungoides/Sezary syndrome, naplastic large cell lymphoma (T-cell type),enteropathy type T-cell lymphoma, adult T-cell leukemia/lymphoma, orangioimmunoblastic T-cell lymphoma.
 39. The method of claim 37, whereinthe anaplastic large cell lymphoma (ALCL) is systemic ALCL or primarycutaneous ALCL.
 40. The method of claim 33, wherein the disease ordisorder is Burkitt's lymphoma, acute myeloblastic leukemia, chronicmyeloid leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, hairy cellleukemia, Mantle cell lymphoma, small lymphocytic lymphoma, follicularlymphoma, xenoderoma pigmentosum, keratoctanthoma, lymphoplasmacyticlymphoma, extranodal marginal zone lymphoma, Waldenstrom'smacroglobulinemia, prolymphocytic leukemia, acute lymphoblasticleukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT)lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoidgranulomatosis, splenic marginal zone lymphoma, primary effusionlymphoma, intravascular large B-cell lymphoma, plasma cell leukemia,extramedullary plasmacytoma, smouldering myeloma (aka asymptomaticmyeloma), monoclonal gammopathy of undetermined significance (MGUS), ordiffuse large B cell lymphoma.
 41. The method of claim 40, wherein thenon-Hodgkin's lymphoma (NHL) is relapsed NHL, refractory NHL,recucurrent follicular NHL, indolent NHL (iNHL), or aggressive NHL(aNHL).
 42. The method of claim 40, wherein the diffuse large B celllymphoma is activated B-cell like (ABC) diffuse large B cell lymphoma,or germinal center B cell (GCB) diffuse large B cell lymphoma.
 43. Themethod of claim 40, wherein the Burkitt's lymphoma is endemic Burkitt'slymphoma, sporadic Burkitt's lymphoma, or Burkitt's-like lymphoma. 44.The method of claim 33, wherein the disease or disorder is rheumatoidarthritis, multiple sclerosis, systemic lupus erythematous, asthma,allergy, allergic rhinitis, pancreatitis, psoriasis, anaphylaxis,glomerulonephritis, inflammatory bowel disease, thrombosis, meningitis,encephalitis, diabetic retinopathy, benign prostatic hypertrophy,myasthenia gravis, Sjögren's syndrome, osteoarthritis, restenosis, oratherosclerosis.
 45. The method of claim 33, wherein the disease ordisorder is heart hypertropy, cardiac myocyte dysfunction, acutecoronary syndrome, chronic obstructive pulmonary disease (COPD), chronicbronchitis, elevated blood pressure, ischemia, ischemia-reperfusion,vasoconstriction, anemia, bacterial infection, viral infection, graftrejection, kidney disease, anaphylactic shock fibrosis, skeletal muscleatrophy, skeletal muscle hypertrophy, angiogenesis, sepsis,graft-versus-host disease, allogeneic or xenogeneic transplantation,glomerulosclerosis, progressive renal fibrosis, idiopathicthrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis,systemic lupus erythematosus, lupus nephritis, pemphigus, or membranousnephropathy.
 46. The method of claim 45, wherein the idiopathicthrombocytopenic purpura (ITP) is relapsed ITP or refractory ITP. 47.The method of claim 45, wherein the vasculitis is Behcet's disease,Cogan's syndrome, giant cell arteritis, polymyalgia rheumatica (PMR),Takayasu's arteritis, Buerger's disease (thromboangiitis obliterans),central nervous system vasculitis, Kawasaki disease, polyarteritisnodosa, Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis(essential or hepatitis C virus (HCV)-induced), Henoch-Schonlein purpura(HSP), hypersensitivity vasculitis, microscopic polyangiitis, Wegener'sgranulomatosis, or anti-neutrophil cytoplasm antibody associated (ANCA)systemic vasculitis (AASV).
 48. The method of claim 33, wherein thedisease or disorder is Alzheimer's disease, central nervous systemtrauma, or stroke.